Taxane coatings for implantable medical devices

ABSTRACT

This disclosure relates to implantable medical devices coated with a taxane therapeutic agent, such as paclitaxel, in one or more solid form(s) having varying dissolution rates. Particularly preferred coatings comprise amorphous and/or solvated solid forms of taxane therapeutic agents that provide durable coatings that release the taxane over a desired period of time, which can be varied in the absence of a polymer by selecting the type and amount of solid forms of the taxane therapeutic agent in the coating. Other preferred embodiments relate to methods of coating medical devices and methods of treatment. The coatings can provide a sustained release of the taxane therapeutic agent within a body vessel without containing a polymer to achieve the desired rate of paclitaxel elution.

RELATED APPLICATIONS

This application in a continuation of U.S. patent application Ser. No.11/715,975, filed Mar. 8, 2007 which claims the benefit of U.S.Provisional Patent Applications: 60/781,264, entitled “Taxane Coatingsfor Implantable Medical Devices” and filed Mar. 10, 2006; 60/830,726,entitled “Controlled Release Taxane Coatings for Implantable Medicaldevices” and filed Jul. 13, 2006; and 60/830,660, entitled “CyclodextrinElution Media for Medical Device Coatings Comprising a TaxaneTherapeutic Agent” and filed Jul. 13, 2006, all of which applicationsare incorporated herein by reference in their entirety.

TECHNICAL FIELD

The present disclosure relates to releasable taxane therapeutic agentcoatings for implantable medical devices, including stents.

BACKGROUND

Delivery of a therapeutic agent from an implantable medical device canbe desirable for a variety of applications. Therapeutic agents can bereleased from a medical device, such as an expandable stent or valve, totreat or mitigate undesirable conditions including restenosis, tumorformation or thrombosis. Procedures for mitigating certain conditionscan include implantation of a device comprising a therapeutic agent. Forexample, the implantation of stents during angioplasty procedures hassubstantially advanced the treatment of occluded body vessels.Angioplasty procedures such as Percutaneous Transluminal CoronaryAngioplasty (PTCA) can widen a narrowing or occlusion of a blood vesselby dilation with a balloon. Occasionally, angioplasty may be followed byan abrupt closure of the vessel or by a more gradual closure of thevessel, commonly known as restenosis. Acute closure may result from anelastic rebound of the vessel wall and/or by the deposition of bloodplatelets and fibrin along a damaged length of the newly opened bloodvessel. In addition, restenosis may result from the natural healingreaction to the injury to the vessel wall (known as intimalhyperplasia), which can involve the migration and proliferation ofmedial smooth muscle cells that continues until the vessel is againoccluded. To prevent such vessel occlusion, stents have been implantedwithin a body vessel. However, restenosis may still occur over thelength of the stent and/or past the ends of the stent where the inwardforces of the stenosis are unopposed. To reduce this problem, one ormore therapeutic agents may be administered to the patient. For example,a therapeutic agent may be administered systemically, locallyadministered through a catheter positioned within the body vessel nearthe stent, or coated on the stent itself.

A medical device can be coated with a therapeutic agent in a mannersuitable to expose tissue near the implantation site of the medicaldevice to the therapeutic agent over a desired time interval, such as byreleasing the therapeutic agent from an implanted stent into surroundingtissue inside a body vessel. Various approaches can be used to controlthe rate and dose of release of therapeutic agents from an implantablemedical device. The design configuration of an implantable device can beadapted to influence the release of therapeutic from the device. Atherapeutic agent can be included in the implantable medical device invarious configurations. In some devices, the therapeutic agent iscontained within an implantable frame or within a coating on the surfaceof the implantable frame. An implantable frame coating can include abioabsorbable material mixed with a therapeutic agent, or coated overthe therapeutic agent. Some implantable medical devices comprise animplantable frame with a porous biostable material mixed with or coatedover a therapeutic agent. Implantable medical devices can also comprisea biostable material containing a dissolvable material and a therapeuticagent, where dissolution of the removable material upon implantationforms pores that release the therapeutic agent.

The design of a controlled release medical device can also depend on thedesired mode of implantation of the device. The device can be adapted tothe appropriate biological environment in which it is used. For example,a coated medical device for percutaneous transcatheter implantation canbe sized and configured for implantation from the distal portion of acatheter, and adapted for expansion at the point of treatment within thebody vessel by balloon or self-expansion. An implantable medical devicecan also be adapted to withstand a desired amount of flexion or impact,and should provide delivery of a therapeutic agent with a desiredelution rate for a desired period of time.

Paclitaxel, and taxane analogues and derivatives thereof, can be used asa therapeutic agent coated on and released from implantable devices,such as stents, to mitigate or prevent restenosis. Paclitaxel isbelieved to disrupt mitosis (M-phase) by binding to tubulin to formabnormal mitotic spindles (i.e., a microtubule stabilizing agent). Atherapeutic compound such as paclitaxel can crystallize as more than onedistinct crystalline species (i.e., having a different arrangement ofmolecules in a solid form) or shift from one crystalline species toanother. This phenomena is known as polymorphism, and the distinctspecies are known as polymorphs. Polymorphs can exhibit differentoptical properties, melting points, solubilities, chemical reactivities,dissolution rates, and different bioavailabilities. Paclitaxel andtaxane derivatives thereof can be formed in an amorphous form, or in atleast two different crystalline polymorphs. Solid forms of paclitaxel atroom temperature include: amorphous paclitaxel (“aPTX”), dihydratecrystalline paclitaxel (“dPTX”) and anhydrous crystalline paclitaxel.These different solid forms of paclitaxel can be characterized andidentified using various solid-state analytical tools, for example asdescribed by Jeong Hoon Lee et al., “Preparation and Characterization ofSolvent Induced Dihydrate, Anhydrous and Amorphous Paclitaxel,” Bull.Korean Chem. Soc. v. 22, no. 8, pp. 925-928 (2001), incorporated hereinby reference in its entirety.

U.S. Pat. No. 6,858,644, filed Nov. 26, 2002 by Benigni et al.(“Benigni”), teaches a crystalline solvate comprising paclitaxel and asolvent selected from the group consisting of dimethylsulfoxide,N,N′-dimethylformamide, N,N′-dimethylacetamide, N-methyl-2-pyrrolidone,1,3-dimethyl-2-imidazolidinone,1,3-dimethyl-3,4,5,6-tetrahydro-2-(1H)-pyrimidinone, and acetonitrileand combinations thereof. However, Benigni does not describe implantabledevice coatings comprising crystalline paclitaxel forms with differentelution rates. Benigni discloses various solid forms of paclitaxel,including a first solid form reported as a highly water insolublecrystalline, granular, solvent-free form. The first solid form issubstantially non-hygroscopic under normal laboratory conditions(relative humidity (RH) approximately 50-60%; 20-30° C.). However, whencontacted with an atmosphere having a relative humidity greater thanabout 90%, or in aqueous suspensions, dispersions or emulsions, thefirst paclitaxel solid form reportedly converts (as a function of time,temperature, agitation, etc.) to a thermodynamically more stable secondsolid form. The second solid form is described as a trihydrateorthorhombic form having six water sites per two independent paclitaxelmolecules (one paclitaxel “dimer”). These hydrated crystals reportedlypresent a fine, hair-like appearance and are even less water solublethan the first solid form. The second solid form is reportedly formed inaqueous suspensions or through crystallization from aqueous solvents inthe presence of a large excess of water. This form is also disclosed inpatent application EP 0 717 041, which describes the second solid formas being characterized by single crystal X-ray diffraction studies asbeing orthorhombic, with unit cells containing two crystallographicallyindependent molecules of paclitaxel associated with hydrogen bonds toform a “dimer”. Mastropaolo, et al. disclosed a crystalline solvate ofpaclitaxel obtained by evaporation of solvent from a solution of Taxol®in dioxane, water and xylene. Proc. Natl. Acad. Sci. USA 92, 6920-24(July, 1995). This solvate is indicated as being unstable, and, in anyevent, has not been shown to effect purification of crude paclitaxel.The thin plate-like crystals are reported to contain five watermolecules and three dioxane molecules per two molecules of paclitaxel.

Many medical device coatings adapted for controlled release of taxanetherapeutic agent such as paclitaxel rely on a polymer coating that ismixed with or applied above and/or beneath the releasable therapeuticagent to regulate the release of the therapeutic agent from the medicaldevice surface. For example, U.S. Pat. No. 6,589,546 to Kamath et al(filed Dec. 10, 2001) and Published US Patent Application 2004/0039441by Rowland et al. (filed May 20, 2003) describe medical device coatingscomprising a therapeutic agent mixed with a polymer to provide acontrolled release of the therapeutic agent. Published US PatentApplication 2003/0236513 by Schwarz et al. (filed Jun. 19, 2002)describes medical device coatings comprising a polymer coating depositedover or mixed with a therapeutic agent to control the rate of release ofthe therapeutic agent from the device.

What is needed are medical devices that permit controlled release of atherapeutic agent as a result of the solid form of the therapeuticagent, with or without a polymer. In particular, there remains a needfor intravascularly-implantable medical devices capable of releasing atherapeutic agent at a desired rate and over a desired time period uponimplantation. Preferably, an implanted medical device releases atherapeutic agent at the site of medical intervention to promote atherapeutically desirable outcome, such as mitigation of restenosis.There is also a need for a medical device with a coating of a releasabletherapeutic agent coating having sufficient durability to resist theundesirable premature release of the therapeutic agent from the deviceprior to implantation at a point of treatment within a body vessel. Inaddition, there is a need for sufficiently durable medical devicecoatings comprising or consisting of a sustained-release taxanetherapeutic agent while being free from a polymer or non-biocompatibleorganic solvents.

SUMMARY

Medical devices comprising a releasable taxane therapeutic agent coatingare provided. The taxane therapeutic agent coating includes one or moretaxane therapeutic agents deposited on the device in one or more solidforms, including various polymorphs or solvated forms of the taxanetherapeutic agent. For example, the taxane therapeutic agent coating canbe deposited as a solvated, crystalline or amorphous solid form, or acombination thereof. These different solid forms of the taxanetherapeutic agent are preferably formed from molecules with identicalmolecular structures arranged differently in the solid coating on themedical device. Some solid forms may further comprise water molecules.Once dissolved, taxane therapeutic agent molecules originating fromdifferent solid forms are indistinguishable after elution into solutionor within the body. However, the taxane solid forms often havemeasurably different rates of elution from the medical device.Therefore, medical device coatings described herein can provide fordesired release rates of a taxane therapeutic agent depending on thenumber and distribution of solid form(s) of the therapeutic agent in thecoating. The coating can have one or more layers. The taxane therapeuticagent coatings can provide controlled release of the taxane therapeuticagent from the medical device from coatings in the absence of a polymerin the coating.

In a first embodiment, solid compositions comprising a taxanetherapeutic agent in one, two or more solid forms are provided. Thecompositions preferably include a single taxane therapeutic agent in twoor more solid forms, although a taxane therapeutic agent coating canoptionally include multiple taxane therapeutic agents. Taxanetherapeutic agent molecules preferably share a common core taxanestructure, but can differ in the arrangement of the taxane molecules inthe various solid forms. The various solid forms of the taxanetherapeutic agent can be characterized and differentiated by one or morephysical properties, including infrared and Raman vibrationalspectroscopy, differing solubilities in various elution media, differentmelting points, X-ray Diffraction (XRD), ¹³C Nuclear Magnetic Resonance(NMR), and/or Temperature Programmed Desorption (TPD). The presence ofdifferent solid forms of the taxane therapeutic agent in a medicaldevice coating are preferably identified by contacting the coating withan elution medium that selectively dissolves one solid form more rapidlythan a second solid form. In solution with an elution medium, such asporcine serum or blood, the presence of the taxane therapeutic agent canbe identified, for example by using ultraviolet (UV) spectroscopy orhigh pressure liquid chromatography (HPLC). For example, in certainelution media such as porcine serum, the dihydrate taxane therapeuticagent structure dissolves more slowly than the amorphous solid form.Preferably, the taxane therapeutic agent is paclitaxel, although thetaxane therapeutic agent may include one or more paclitaxel analog orderivative. The medical device coating can include any suitableamount(s) of one or more of the taxane solid forms that provide adesired elution rate of the taxane therapeutic agent, while alsopreferably having a desired durability and suitable level of surfaceuniformity.

In a first aspect, the first embodiment provides a medical devicecoating composition including a taxane therapeutic agent in a solvatecrystal solid form. Preferably, the solvate structure is a dihydratetaxane structure. In a second aspect, the medical device coatingcomposition includes an amorphous taxane solid form. In a third aspect,the medical device coating composition includes an anhydrous taxanesolid form. In a fourth aspect, the medical device coating compositionincludes a two or more solid forms of a taxane therapeutic agent, withthe different solid forms provided in the same layer of a coating or inseparate coating layers. A single-layer coating can comprise a mixtureof a taxane therapeutic agent in the dihydrate taxane crystalline solidform and the taxane therapeutic agent configured in the amorphous taxanesolid form. Preferably, the coating is free of a polymer, or containsless than about 0.10 μg of any polymer per mm² of abluminal surface areaand preferably less than a total of 1 μg of any polymer in the entirecoating. Accordingly, taxane therapeutic agent coatings with desirableelution rates can be obtained without including a polymer coatingcomponent in contact with the therapeutic agent.

In a second embodiment, an implantable medical device is provided with acoating that includes one or more layers each comprising or consistingessentially of a taxane therapeutic agent in one or more solid forms.The solid forms of the taxane therapeutic agent coating can includeamorphous, anhydrous or a solvated taxane therapeutic agent. Preferably,the solid form of the taxane therapeutic agent includes an amorphoustaxane structure, an anhydrous taxane structure, a dihydrate solvatetaxane structure, or a combination of two or more of these solid forms.In a first aspect, the second embodiment provides medical devicecoatings having a one or more layers comprising or consisting of ataxane therapeutic agent in a single solid form. The solid form ispreferably an amorphous or anhydrous polymorph or dihydrate solvatedform of the taxane therapeutic agent. In a second aspect, the secondembodiment provides medical device coatings having a one or more layerscomprising or consisting of a mixture of a taxane therapeutic agent intwo or more solid forms. In a third aspect, the second embodimentprovides medical device coatings having at least two layers, wherein thesecond coating consists essentially of a taxane therapeutic agent in afirst solid form, and the second coating comprises or consistsessentially of the taxane therapeutic agent in a second solid form.Optionally, the first layer and/or the second layer can include amixture of two or more solid forms of the taxane therapeutic agent.

In a third embodiment, methods of coating taxane therapeutic agents on amedical device are provided. In one aspect, methods of depositing acoating comprising a solvate solid form of a taxane therapeutic agent,such as a dihydrate solid form, are provided. For example, methods fordepositing a paclitaxel dihydrate or single-layer mixtures of paclitaxeldihydrate and amorphous paclitaxel are particularly preferred. Thetaxane therapeutic agent is preferably deposited on a medical device byspraying a solution of the therapeutic agent using a pressure,ultrasonic or electrostatic spray apparatus. Different solid forms ofthe taxane therapeutic agent can be deposited in one or more layers onthe medical device by changing the solvent system or the spray coatingparameters used in the spray deposition process.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1A shows a coated implantable medical device.

FIG. 1B shows a cross sectional view of a portion of the medical deviceof FIG. 1A.

FIG. 2 shows an ultraviolet (UV) absorption spectrum of paclitaxel inethanol.

FIG. 3A shows an infrared spectrum of a first solid form of paclitaxel.

FIG. 3B shows an infrared spectrum of a second solid form of paclitaxel.

FIG. 3C shows an infrared spectrum of a third solid form of paclitaxel.

FIG. 4A shows a series of confocal Raman spectra for various solid formsof paclitaxel.

FIG. 4B shows the spatial distribution of two different solid forms ofpaclitaxel as a function of coating depth, obtained using confocal Ramanspectroscopy.

FIG. 5A shows a powder X-ray diffraction (XRPD) spectrum of twodifferent solid forms of paclitaxel.

FIG. 5B shows a ¹³C NMR spectrum of three different solid forms ofpaclitaxel.

FIG. 6A shows elution profiles for two different coatings of amorphouspaclitaxel and solvated paclitaxel eluting in porcine serum.

FIG. 6B shows elution profiles for two different coatings eachcomprising different amounts of the amorphous and dihydrate solid formsof paclitaxel eluting in porcine serum.

FIG. 6C shows elution profiles for several different coatings havingdifferent amounts of the amorphous paclitaxel and dihydrate solid formsof paclitaxel eluting in an aqueous solution comprisingHeptakis-(2,6-di-O-methyl)-β-cyclodextrin (HCD).

FIG. 7A shows an elution profile for a coating of the amorphous solidform of paclitaxel eluting in sodium dodecyl sulfate (SDS).

FIG. 7B shows the elution profile for a coating of the dihydrate solidform of paclitaxel eluting in sodium dodecyl sulfate (SDS).

FIG. 8A is a kinetic plot for the dissolution of amorphous paclitaxel inporcine serum.

FIG. 8B is a kinetic plot for the dissolution of dihydrate paclitaxel inporcine serum.

FIG. 9 is a graph of calculated (predicted) porcine serum solubility ofa paclitaxel coating comprising varying amounts of the dihydratepaclitaxel and the amorphous paclitaxel.

FIG. 10A and FIG. 10B are optical micrographs of a paclitaxel coatedstent.

FIG. 11A and FIG. 11B are optical micrographs of a paclitaxel coatedstent.

FIG. 12A and FIG. 12B are optical micrographs of a paclitaxel coatedstent.

FIG. 13A and FIG. 13B are optical micrographs of a paclitaxel coatedstent.

FIG. 14 is a graph showing the elution profiles of two differentpaclitaxel coated stents, described in Example 6.

FIG. 15 is a graph showing the elution profiles from two differentpaclitaxel coated stents, described in Example 7.

DETAILED DESCRIPTION

The present invention relates to medical device coatings that include ataxane therapeutic agent. Preferred compositions comprise one or moretaxanes in one or more solid forms selected to provide desiredproperties of dissolution rate and/or durability. The coatings arepreferably substantially free of a polymer, and may consist only oftaxane therapeutic agent(s) in one or more solid forms. One particularlypreferred taxane therapeutic agent is paclitaxel. Unless otherwisespecified, description of paclitaxel coatings herein relate to apreferred embodiment of the taxane therapeutic agent, and is intended tobe illustrative of all taxane therapeutic agents capable of forming thesolvate and polymorph solid forms described, without limiting the scopeof the therapeutic agent to paclitaxel.

Certain preferred embodiments provide an implantable medical device(“medical device”) allowing for the release of a taxane therapeuticagent into the adjacent or surrounding tissue upon implantation. Thetaxane therapeutic agent is preferably paclitaxel, or aderivative/analog thereof, releasably coated on at least a portion ofthe abluminal surface of the medical device. Preferably, the coatingconsists essentially of the taxane therapeutic agent, and does notinclude a material, such as a polymer or non-polymer carrier, to modifythe rate of release of the therapeutic agent. In particular, the coatingis preferably free of a polymer, or contains less than about 0.50 μg,0.10 μg or 0.05 μg of a polymer per mm² of abluminal surface area andpreferably less than 10 μg, 5 μg, 1 μg or 0.5 μg of a polymer total inthe coating. Most preferably, the coating is free of a polymer, orcontains less than about 0.50 μg, 0.10 μg or 0.05 μg of any polymer permm² of abluminal surface area and preferably less than 10 μg, 5 μg, 1 μgor 0.5 μg of any polymer total in the coating.

The rate of release of the paclitaxel therapeutic agent from the medicaldevice can be altered by providing a coating including varying amountsof the one or more paclitaxel polymorph compositions releasably attachedto the medical device. For example, the rate of release of paclitaxelcan be extended by providing paclitaxel coatings with the dihydratesolid form of paclitaxel, alone or in combination with other paclitaxelsolid forms. Optionally, one or more solid forms of paclitaxel can beincluded in separate coating layers on the surface of, or within holesor wells formed in, medical device. Desirably, the medical devicecomprises materials configured to provide for release of a paclitaxeltherapeutic agent within a body vessel according to a therapeuticallyeffective elution profile.

Definitions

Unless otherwise defined, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention pertains. In case of conflict, thepresent document, including definitions, will control. Preferred methodsand materials are described below, although methods and materialssimilar or equivalent to those described herein can be used in thepractice or testing of the present invention. All publications, patentapplications, patents and other references mentioned herein areincorporated by reference in their entirety. The materials, methods, andexamples disclosed herein are illustrative only and not intended to belimiting.

The term “hydrophobic,” as used herein, refers to a substance with asolubility in water of less than 0.1 mg/mL at room temperature (about25° C.).

A therapeutic agent is “enclosed” if the therapeutic agent is surroundedby the coating or other portions of the medical device, and does notform a portion of the surface area of the medical device prior torelease of the therapeutic agent. When a medical device is initiallyplaced in an elution medium, an enclosed therapeutic agent is preferablynot initially in contact with the elution medium.

The term “elution,” as used herein, refers to removal of a material froma substrate by contact with an elution medium. The elution medium canremove the material from the substrate by any process, including byacting as a solvent with respect to the removable material. For example,in medical devices adapted for introduction to the vascular system,blood can act as an elution medium that dissolves a therapeutic agentreleasably associated with a portion of the surface of the medicaldevice. The therapeutic agent can be selected to have a desiredsolubility in a particular elution medium. Unless otherwise indicated,the term “release” referring to the removal of the therapeutic agentfrom a coating in contact with an elution medium is intended to besynonymous with the term “elution” as defined above. Similarly, an“elution profile” is intended to be synonymous with a “release profile,”unless otherwise indicated.

An “elution medium,” as used herein, refers to a material (e.g. a fluid)or environment that releases a therapeutic agent from a coating uponcontact of the coating with the elution medium for a desired period oftime. A suitable elution medium is any substance or environment intowhich the therapeutic agent can be released. The elution medium isdesirably a fluid. More desirably, the elution medium is a biologicalfluid such as blood or porcine serum, although any other chemicalsubstance can be used as an elution medium. For example, alternativeelution media include phosphate buffered saline, blood, a cyclodextrinsuch as Heptakis-(2,6-di-O-methyl)-β-cyclodextrin (HCD), Sodium DodecylSulfate (SDS), aqueous solutions, reaction conditions includingtemperature and/or pH, or combinations thereof, that release thetherapeutic agent at a desired rate. Preferably, the elution medium is afluid that provides an elution profile that is similar to the elutionprofile obtained upon implantation of the medical device within a bodyvessel and/or a desired time period for elution. For example, porcineserum can provide an elution profile that is similar to the elutionprofile in blood for some coating configurations.

The term “effective amount” refers to an amount of an active ingredientsufficient to achieve a desired affect without causing an undesirableside effect. In some cases, it may be necessary to achieve a balancebetween obtaining a desired effect and limiting the severity of anundesired effect. It will be appreciated that the amount of activeingredient used will vary depending upon the type of active ingredientand the intended use of the composition of the present invention.

The terms “about” or “substantially” used with reference to a quantityincludes variations in the recited quantity that are equivalent to thequantity recited, such as an amount that is insubstantially differentfrom a recited quantity for an intended purpose or function.

The term “luminal surface,” as used herein, refers to the portion of thesurface area of a medical device defining at least a portion of aninterior lumen. Conversely, the term “abluminal surface,” as usedherein, refers to portions of the surface area of a medical device thatdo not define at least a portion of an interior lumen. For example,where the medical device is a tubular frame formed from a plurality ofinterconnected struts and bends defining a cylindrical lumen, theabluminal surface can include the exterior surface, sides and edges ofthe struts and bends, while the luminal surface can include the interiorsurface of the struts and bends.

The term “interface,” as used herein, refers to a common boundarybetween two structural elements, such as two coating layers in contactwith each other.

The term “coating,” as used herein and unless otherwise indicated,refers generally to material attached to an implantable medical device.A coating can include material covering any portion of a medical device,and can be configured as one or more coating layers. A coating can havea substantially constant or a varied thickness and composition. Coatingscan be adhered to any portion of a medical device surface, including theluminal surface, the abluminal surface, or any portions or combinationsthereof.

The term “coating layer,” as used herein, refers to a stratified portionof a coating having a measurable composition. Coating layers may beidentified by one or more measurable properties (such as rate ofelution, appearance, durability, infrared spectrum, etc.), and may bedifferentiated from an adjacent coating layer by at least one measurableproperty (e.g. different elution rates). Coating layers aresubstantially parallel to typically oriented a substrate surface. Acoating layer material can be positioned in contact with the substratesurface, or in contact with other material(s) between the substratesurface and the coating layer material. A coating layer can cover anyportion of the surface of a substrate, including material positioned inseparate discrete portions of the substrate or a continuous layer overan entire substrate surface.

The term “implantable” refers to an ability of a medical device to bepositioned at a location within a body, such as within a body vessel.Furthermore, the terms “implantation” and “implanted” refer to thepositioning of a medical device at a location within a body, such aswithin a body vessel.

The term “alloy” refers to a substance composed of two or more metals orof a metal and a nonmetal intimately united, such as by chemical orphysical interaction. Alloys can be formed by various methods, includingbeing fused together and dissolving in each other when molten, althoughmolten processing is not a requirement for a material to be within thescope of the term “alloy.” As understood in the art, an alloy willtypically have physical or chemical properties that are different fromits components.

The term “mixture” refers to a combination of two or more substances inwhich each substance retains its own chemical identity and properties.

The terms “absorption,” “bioresorption” and “bioabsorption”can be usedinterchangeably to refer to the ability of the polymer or itsdegradation products to be removed by biological events, such as byfluid transport away from the site of implantation or by cellularactivity (e.g., phagocytosis). The term “bioabsorbable” will generallybe used in the following description to encompass resorbable,absorbable, bioresorbable, and biodegradable.

A “biocompatible” material is a material that is compatible with livingtissue or a living system by not being toxic or injurious.

A “non-bioabsorbable” or “biostable” material refers to a material, suchas a polymer or copolymer, which remains in the body without substantialbioabsorption.

The phrase “controlled release” refers to an alteration of the rate ofrelease of a therapeutic agent from a medical device coating in a givenenvironment. A coating or configuration that alters the rate at whichthe therapeutic agent is released from a medical device provides for thecontrolled release of the therapeutic agent. A “sustained release”refers to prolonging the rate or duration of release of a therapeuticagent from a medical device. The rate of a controlled release of atherapeutic agent may be constant or vary with time. A controlledrelease may be described with respect to a drug elution profile, whichshows the measured rate at which the therapeutic agent is removed from adrug-coated device in a given elution medium (e.g., solvent) as afunction of time. A controlled release elution profile may include, forexample, an initial burst release associated with the introduction ofthe medical device into the physiological environment, followed by amore gradual subsequent release. A controlled release can also be agradient release in which the concentration of the therapeutic agentreleased varies over time or a steady state release in which thetherapeutic agent is released in equal amounts over a certain period oftime (with or without an initial burst release).

As used herein, the phrase “therapeutic agent” refers to any implantablepharmaceutically active agent intended to provide therapeutic effect onthe body to treat or prevent conditions or diseases.

An “anti-proliferative” agent indicates any molecule that acts toinhibit cell proliferative events. Examples of anti-proliferative agentsinclude microtubule inhibitors such as vinblastine, vincristine,colchicine and paclitaxel, or other agents such as cisplatin.

The term “pharmaceutically acceptable,” as used herein, refers to thosecompounds of the present invention which are, within the scope of soundmedical judgment, suitable for use in contact with the tissues of humansand lower mammals without undue toxicity, irritation, and allergicresponse, are commensurate with a reasonable benefit/risk ratio.

When naming substances that can exist in multiple enantiomeric forms,reference to the name of the substance without an enantiomericdesignation, such as (d) or (l), refers herein to the genus ofsubstances including the (d) form, the (l) form and the racemic mixture(e.g., d,l), unless otherwise specified. For example, recitation of“poly(lactic acid),” unless otherwise indicated, refers to a compoundselected from the group consisting of: poly(L-lactic acid),poly(D-lactic acid) and poly(D,L-lactic acid). Similarly, genericreference to compounds that can exist in two or more polymorphs isunderstood to refer to the genus consisting of each individual polymorphspecies and any combinations or mixtures thereof.

As used herein, “derivative” refers to a chemically or biologicallymodified version of a chemical compound that is structurally similar toa parent compound and (actually or theoretically) derivable from thatparent compound. A derivative may or may not have different chemical orphysical properties of the parent compound. For example, the derivativemay be more hydrophilic or it may have altered reactivity as compared tothe parent compound. Derivatization (i.e., modification) may involvesubstitution of one or more moieties within the molecule (e.g., a changein functional group). For example, a hydrogen may be substituted with ahalogen, such as fluorine or chlorine, or a hydroxyl group (—OH) may bereplaced with a carboxylic acid moiety (—COOH). The term “derivative”also includes conjugates, and prodrugs of a parent compound (i.e.,chemically modified derivatives which can be converted into the originalcompound under physiological conditions). For example, the prodrug maybe an inactive form of an active agent. Under physiological conditions,the prodrug may be converted into the active form of the compound.Prodrugs may be formed, for example, by replacing one or two hydrogenatoms on nitrogen atoms by an acyl group (acyl prodrugs) or a carbamategroup (carbamate prodrugs). More detailed information relating toprodrugs is found, for example, in Fleisher et al., Advanced DrugDelivery Reviews 19 (1996) 115; Design of Prodrugs, H. Bundgaard (ed.),Elsevier, 1985; or H. Bundgaard, Drugs of the Future 16 (1991) 443. Theterm “derivative” is also used to describe all solvates, for examplehydrates or adducts (e.g., adducts with alcohols), active metabolites,and salts of the parent compound. The type of salt that may be prepareddepends on the nature of the moieties within the compound. For example,acidic groups, for example carboxylic acid groups, can form alkali metalsalts or alkaline earth metal salts (e.g., sodium salts, potassiumsalts, magnesium salts and calcium salts, as well as salts withphysiologically tolerable quaternary ammonium ions and acid additionsalts with ammonia and physiologically tolerable organic amines such astriethylamine, ethanolamine or tris-(2-hydroxyethyl)amine). Basic groupscan form acid addition salts, for example with inorganic acids such ashydrochloric acid, sulfuric acid or phosphoric acid, or with organiccarboxylic acids and sulfonic acids such as acetic acid, citric acid,benzoic acid, maleic acid, fumaric acid, tartaric acid, methanesulfonicacid or p-toluenesulfonic acid. Compounds which simultaneously contain abasic group and an acidic group, for example a carboxyl group inaddition to basic nitrogen atoms, can be present as zwitterions. Saltscan be obtained by customary methods known to those skilled in the art,for example by combining a compound with an inorganic or organic acid orbase in a solvent or diluent, or from other salts by cation exchange oranion exchange.

As used herein, “analog” or “analogue” refer to a chemical compound thatis structurally similar to another but differs slightly in composition(as in the replacement of one atom by an atom of a different element orin the presence of a particular functional group), but may or may not bederivable from the parent compound. A “derivative” differs from an“analog” in that a parent compound may be the starting material togenerate a “derivative,” whereas the parent compound may not necessarilybe used as the starting material to generate an “analogue.”

Any concentration ranges, percentage range, or ratio range recitedherein are to be understood to include concentrations, percentages orratios of any integer within that range and fractions thereof, such asone tenth and one hundredth of an integer, unless otherwise indicated.Also, any number range recited herein relating to any physical feature,such as polymer subunits, size or thickness, are to be understood toinclude any integer within the recited range, unless otherwiseindicated. It should be understood that the terms “a” and “an” as usedabove and elsewhere herein refer to “one or more” of the enumeratedcomponents. For example, “a” polymer refers to one polymer or a mixturecomprising two or more polymers.

As used herein, the term “solid form” in reference to a taxane moleculesrefers to an arrangement of molecules comprising a core taxane structurein the solid phase, including any polymorph or solvate crystal solidstructure. Solid forms can include crystalline or non-crystallinemolecular arrangements. Examples of solid forms of taxane moleculesinclude anhydrous paclitaxel, amorphous paclitaxel and dihydratepaclitaxel.

As used herein, the term “polymorph” refers to a particular solid formof a taxane therapeutic agent, having particular physical propertiessuch as X-ray diffraction, IR spectra, melting point, and the like.Polymorphs include solvate crystalline solid forms, amorphous solidforms and anhydrous solid forms of a taxane therapeutic agent. Thepolymorphs may have asymmetric centers, chiral axes, and chiral planes(as described in: E. L. Eliel and S. H. Wilen, Stereochemistry of CarbonCompounds, John Wiley & Sons, New York, 1994, pages 1119-1190), andoccur as racemates, racemic mixtures, and as individual diastereomers,with all possible isomers and mixtures thereof, including opticalisomers. In addition, the polymorphs disclosed herein may exist astautomers and both tautomeric forms are intended to be encompassed bythe scope of the invention, even though only one tautomeric structure isdepicted.

Taxane Therapeutic Agents

The present invention relates to compositions comprising taxanetherapeutic agents (“taxanes”), such as paclitaxel. Taxanes in generaland paclitaxel in particular, are taxane therapeutic compoundsconsidered to function as a cell cycle inhibitors by acting as ananti-microtubule agent, and more specifically as a stabilizer. As usedherein, the term “paclitaxel” refers to a compound of the chemicalstructure shown as structure (1) below, consisting of a core structurewith four fused rings (“core taxane structure,” shaded in structure(1)), with several substituents.

Other taxane analog or derivative compounds are characterized byvariation of the paclitaxel structure (1). Preferred taxane analogs andderivatives core vary the substituents attached to the core taxanestructure. In one embodiment, the therapeutic agent is a taxane analogor derivative including the core taxane structure (1) and the methyl3-(benzamido)-2-hydroxy-3-phenylpropanoate moiety (shown in structure(2) below) at the 13-carbon position (“C13”) of the core taxanestructure (outlined with a dashed line in structure (1)).

It is believed that structure (2) at the 13-carbon position of the coretaxane structure plays a role in the biological activity of the moleculeas a cell cycle inhibitor. Examples of therapeutic agents havingstructure (2) include paclitaxel (Merck Index entry 7117), docetaxol(TAXOTERE, Merck Index entry 3458), and3′-desphenyl-3′-(4-ntirophenyl)-N-debenzoyl-N-(t-butoxycarbonyl)-10-deacetyltaxol.

Representative examples of paclitaxel derivatives or analogues that canbe used as therapeutic agents include 7-deoxy-docetaxol,7,8-cyclopropataxanes, N-substituted 2-azetidones, 6,7-epoxypaclitaxels, 6,7-modified paclitaxels, 10-desacetoxytaxol,10-deacetyltaxol (from 10-deacetylbaccatin III), phosphonooxy andcarbonate derivatives of taxol, taxol 2′,7-di(sodium1,2-benzenedicarboxylate,10-desacetoxy-11,12-dihydrotaxol-10,12(18)-diene derivatives,10-desacetoxytaxol, Protaxol (2′- and/or 7-O-ester derivatives), (2′-and/or 7-O-carbonate derivatives), asymmetric synthesis of taxol sidechain, fluoro taxols, 9-deoxotaxane, (13-acetyl-9-deoxobaccatine III,9-deoxotaxol, 7-deoxy-9-deoxotaxol, 10-desacetoxy-7-deoxy-9-deoxotaxol),derivatives containing hydrogen or acetyl group and a hydroxy andtert-butoxycarbonylamino, sulfonated 2′-acryloyltaxol and sulfonated2′-O-acyl acid taxol derivatives, succinyltaxol, 2′-γ-aminobutyryltaxolformate, 2′-acetyl taxol, 7-acetyl taxol, 7-glycine carbamate taxol,2′-OH-7-PEG(5000) carbamate taxol, 2′-benzoyl and 2′,7-dibenzoyl taxolderivatives, other prodrugs (2′-acetyltaxol; 2′,7-diacetyltaxol;2′succinyltaxol; 2′-(beta-alanyl)-taxol); 2′gamma-aminobutyryltaxolformate; ethylene glycol derivatives of 2′-succinyltaxol;2′-glutaryltaxol; 2′-(N,N-dimethylglycyl)taxol;2′-(2-(N,N-dimethylamino)propionyl)taxol; 2′orthocarboxybenzoyl taxol;2′aliphatic carboxylic acid derivatives of taxol, Prodrugs{2′(N,N-diethylaminopropionyl)taxol, 2′(N,N-dimethylglycyl)taxol,7(N,N-dimethylglycyl)taxol, 2′,7-di-(N,N-dimethylglycyl)taxol,7(N,N-diethylaminopropionyl)taxol,2′,7-di(N,N-diethylaminopropionyl)taxol, 2′-(L-glycyl)taxol,7-(L-glycyl)taxol, 2′,7-di(L-glycyl)taxol, 2′-(L-alanyl)taxol,7-(L-alanyl)taxol, 2′,7-di(L-alanyl)taxol, 2′-(L-leucyl)taxol,7-(L-leucyl)taxol, 2′,7-di(L-leucyl)taxol, 2′-(L-isoleucyl)taxol,7-(L-isoleucyl)taxol, 2′,7-di(L-isoleucyl)taxol, 2′-(L-valyl)taxol,7-(L-valyl)taxol, 2′7-di(L-valyl)taxol, 2′-(L-phenylalanyl)taxol,7-(L-phenylalanyl)taxol, 2′,7-di(L-phenylalanyl)taxol,2′-(L-prolyl)taxol, 7-(L-prolyl)taxol, 2′,7-di(L-prolyl)taxol,2′-(L-lysyl)taxol, 7-(L-lysyl)taxol, 2′,7-di(L-lysyl)taxol,2′-(L-glutamyl)taxol, 7-(L-glutamyl)taxol, 2′,7-di(L-glutamyl)taxol,2′-(L-arginyl)taxol, 7-(L-arginyl)taxol, 2′,7-di(L-arginyl)taxol}, taxolanalogues with modified phenylisoserine side chains, TAXOTERE,(N-debenzoyl-N-tert-(butoxycaronyl)-10-deacetyltaxol, and taxanes (e.g.,baccatin III, cephalomannine, 10-deacetylbaccatin III, brevifoliol,yunantaxusin and taxusin); and other taxane analogues and derivatives,including 14-beta-hydroxy-10 deacetybaccatin III, debenzoyl-2-acylpaclitaxel derivatives, benzoate paclitaxel derivatives, phosphonooxyand carbonate paclitaxel derivatives, sulfonated 2′-acryloyltaxol;sulfonated 2′-O-acyl acid paclitaxel derivatives, 18-site-substitutedpaclitaxel derivatives, chlorinated paclitaxel analogues, C4 methoxyether paclitaxel derivatives, sulfenamide taxane derivatives, brominatedpaclitaxel analogues, Girard taxane derivatives, nitrophenyl paclitaxel,10-deacetylated substituted paclitaxel derivatives, 14-beta-hydroxy-10deacetylbaccatin III taxane derivatives, C7 taxane derivatives, C10taxane derivatives, 2-debenzoyl-2-acyl taxane derivatives, 2-debenzoyland -2-acyl paclitaxel derivatives, taxane and baccatin III analoguesbearing new C2 and C4 functional groups, n-acyl paclitaxel analogues,10-deacetylbaccatin III and 7-protected-10-deacetylbaccatin IIIderivatives from 10-deacetyl taxol A, 10-deacetyl taxol B, and10-deacetyl taxol, benzoate derivatives of taxol, 2-aroyl-4-acylpaclitaxel analogues, orthro-ester paclitaxel analogues, 2-aroyl-4-acylpaclitaxel analogues and 1-deoxy paclitaxel and 1-deoxy paclitaxelanalogues.

A composition comprising a taxane compound can include formulations,prodrugs, analogues and derivatives of paclitaxel such as, for example,TAXOL (Bristol Myers Squibb, New York, N.Y.), TAXOTERE (AventisPharmaceuticals, France), docetaxel, 10-desacetyl analogues ofpaclitaxel and 3′N-desbenzoyl-3′N-t-butoxy carbonyl analogues ofpaclitaxel. Paclitaxel has a molecular weight of about 853 amu, and maybe readily prepared utilizing techniques known to those skilled in theart (see, e.g., Schiff et al., Nature 277: 665-667, 1979; Long andFairchild, Cancer Research 54: 4355-4361, 1994; Ringel and Horwitz, J.Nat'l Cancer Inst. 83 (4): 288-291, 1991; Pazdur et al., Cancer Treat.Rev. 19 (4): 351-386, 1993; WO 94/07882; WO 94/07881; WO 94/07880; WO94/07876; WO 93/23555; WO 93/10076; WO94/00156; WO 93/24476; EP 590267;WO 94/20089; U.S. Pat. Nos. 5,294,637; 5,283,253; 5,279,949; 5,274,137;5,202,448; 5,200,534; 5,229,529; 5,254,580; 5,412,092; 5,395,850;5,380,751; 5,350,866; 4,857,653; 5,272,171; 5,411,984; 5,248,796;5,248,796; 5,422,364; 5,300,638; 5,294,637; 5,362,831; 5,440,056;4,814,470; 5,278,324; 5,352,805; 5,411,984; 5,059,699; 4,942,184;Tetrahedron Letters 35 (52): 9709-9712, 1994; J. Med. Chem. 35:4230-4237, 1992; J. Med. Chem. 34: 992-998, 1991; J. Natural Prod. 57(10): 1404-1410, 1994; and J. Natural Prod. 57 (11): 1580-1583, 1994; J.Am. Chem. Soc. 110: 6558-6560, 1988), or obtained from a variety ofcommercial sources, including for example, Sigma Chemical Co., St.Louis, Mo. (T7402—from Taxus brevifolia).

In one aspect, the therapeutic agent is selected from the taxaneanalogues and derivatives disclosed in U.S. Pat. No. 5,440,056 as havingthe structure (3):

wherein X may be oxygen (paclitaxel), hydrogen (9-deoxy derivatives),thioacyl, or dihydroxyl precursors; R₁ is selected from paclitaxel orTAXOTERE side chains or alkanoyl of the formula (4):

wherein R₇ is selected from hydrogen, alkyl, phenyl, alkoxy, amino,phenoxy (substituted or unsubstituted); R₈ is selected from hydrogen,alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, phenyl (substituted orunsubstituted), alpha or beta-naphthyl; and R₉ is selected fromhydrogen, alkanoyl, substituted alkanoyl, and aminoalkanoyl; wheresubstitutions refer to hydroxyl, sulfhydryl, allalkoxyl, carboxyl,halogen, thioalkoxyl, N,N-dimethylamino, alkylamino, dialkylamino,nitro, and —OSO₃H, and/or may refer to groups containing suchsubstitutions; R₂ is selected from hydrogen or oxygen-containing groups,such as hydrogen, hydroxyl, alkoyl, alkanoyloxy, aminoalkanoyloxy, andpeptidyalkanoyloxy; R₃ is selected from hydrogen or oxygen-containinggroups, such as hydrogen, hydroxyl, alkoyl, alkanoyloxy,aminoalkanoyloxy, and peptidyalkanoyloxy, and may further be a silylcontaining group or a sulphur containing group; R₄ is selected fromacyl, alkyl, alkanoyl, aminoalkanoyl, peptidylalkanoyl and aroyl; R₅ isselected from acyl, alkyl, alkanoyl, aminoalkanoyl, peptidylalkanoyl andaroyl; R₆ is selected from hydrogen or oxygen-containing groups, such ashydrogen, hydroxyl alkoyl, alkanoyloxy, aminoalkanoyloxy, andpeptidyalkanoyloxy.

In one aspect, the therapeutic agent is selected from the paclitaxelanalogues and derivatives disclosed in PCT International PatentApplication No. WO 93/10076 as cell cycle inhibitors. The analogue orderivative may have a side chain attached to the taxane nucleus at C13,as shown in the structure below (formula 5), in order to conferantitumor activity to the taxane.

WO 93/10076 discloses that the taxane nucleus may be substituted at anyposition with the exception of the existing methyl groups. Thesubstitutions may include, for example, hydrogen, alkanoyloxy,alkenoyloxy, aryloyloxy. In addition, oxo groups may be attached tocarbons labeled 2, 4, 9, and/or 10. As well, an oxetane ring may beattached at carbons 4 and 5. As well, an oxirane ring may be attached tothe carbon labeled 4. In one aspect, the taxane-based cell cycleinhibitor useful in the present invention is disclosed in U.S. Pat. No.5,440,056, which discloses 9-deoxo taxanes. These are compounds lackingan oxo group at the carbon labeled 9 in the taxane structure shown abovein formula (5). The taxane ring may also be substituted at the carbonslabeled 1, 7 and 10 (independently) with H, OH, O—R, or O—CO—R where Ris an alkyl or an aminoalkyl. As well, it may be substituted at carbonslabeled 2 and 4 (independently) with aryol, alkanoyl, aminoalkanoyl oralkyl groups. The side chain of formula (4) may be substituted at R₇ andR₈ (independently) with phenyl rings, substituted phenyl rings, linearalkanes/alkenes, and groups containing H, O or N. R₉ may be substitutedwith H, or a substituted or unsubstituted alkanoyl group.

Taxane Therapeutic Agent Coating Configurations

Various medical devices having a coating comprising a taxane therapeuticagent are provided. The medical device preferably comprises a coatinghaving one or more layers. Preferably, the coating includes one or moresolid forms of a taxane therapeutic agent described with respect to thefirst embodiment.

FIG. 1A shows a coated medical device comprising a self-expandingvascular stent 10 having a luminal surface 12 and a coating 37 appliedto the abluminal surface 14. The vascular stent 10 extends from aproximal end 13 to a distal end 15. The vascular stent 10 has a tubularshape formed from a series of joined hoops 16 formed from interconnectedstruts 17 and bends 18, and defines the interior lumen. FIG. 1B shows across section along line A-A′ of coated strut 17′ from the vascularstent 10 shown in FIG. 1A. Referring to FIG. 1B, the strut 17′ can haveany suitable cross sectional configuration, such as a rectangular crosssection, and can be formed from any suitable material 27 such as anickel titanium alloy, stainless steel or a cobalt chromium alloy. Theabluminal surface 14′, including the proximal edge 13′ and distal edge15′, are coated with the coating 37 adhered to the abluminal surface ofthe vascular stent 10. Preferably, the coating 37 includes one or moresolid forms of a taxane therapeutic agent, such as paclitaxel. In oneaspect, the coating 37 can consist essentially of a single solid form ofthe taxane therapeutic agent, such as a dihydrate solvated paclitaxel.In another aspect, the coating 37 includes a single layer comprising amixture of two or more solid forms of the taxane therapeutic agent, suchas a mixture of dihydrate solvated paclitaxel and amorphous paclitaxel.In yet another aspect, the coating 37 can include two or more coatinglayers each comprising one or more solid forms of the taxane therapeuticagent. Each coating layer may be distinguished, for example, bydifferent elution rates resulting from different solid form structure(s)in each layer. The coating 37 can also include non-taxane components,such as biostable or bioabsorbable polymers, in separate layers from orcombined with a taxane therapeutic agent.

The coating is preferably a single-layer of a therapeutically effectiveamount of the taxane therapeutic agent. Preferably, the single-layerconsists of the taxane therapeutic agent in one or more solid forms. Thetherapeutically effective amount can depend upon the type and severityof the condition to be treated; the type and activity of the specifictherapeutic agent employed; the method by which the medical device isadministered to the patient; the age, body weight, general health,gender and diet of the patient; the time of administration, route ofadministration, and rate of excretion of the specific compound employed;the duration of the treatment; drugs used in combination or coincidentalwith the specific compound employed; and like factors well known in themedical arts.

To obtain the desired dosage of therapeutic agent, the solid form of thetaxane therapeutic agent in the coating may be varied. In oneembodiment, the coating contains from about 0.01 μg to about 10 μg ofthe taxane therapeutic agent per mm² of the surface area of thestructure, preferably about 0.05 μg to about 5 μg, about 0.03 μg toabout 3 μg, about 0.05 μg to about 3 μg, about 0.5 μg to about 4.0 μg,most preferably between about 0.5 and 3.0 μg, of the taxane therapeuticagent per mm² of the abluminal surface area of the structure. Desirably,a total of about 1-500 μg of a taxane therapeutic agent (such aspaclitaxel) is coated on one or more surface of a medical device.

The thickness of the coating layer comprising the taxane therapeuticagent is between 0.1 μm and 20 μm, between 0.1 μm and 10 μm, or between0.1 μm and 5 μm. For the purposes of local delivery from a stent, thedaily dose that a patient will receive depends at least on the length ofthe stent. The total coating thickness is preferably about 50 μm orless, preferably less than about 20 μm and most preferably about 0.1-10μm.

For example, a 6×20 mm stent may be coated with about 0.05-5 μg/mm² ofpaclitaxel, more preferably about 0.5-3 μg/mm², can be applied to theabluminal surface of the stent. Particularly preferred doses of a taxanetherapeutic agent on the abluminal surface of a stent include: 0.06,0.30, 1.00 and 3.00 μg/mm². In another embodiment, the abluminal side ofa 6×20 mm stent (surface area of about 73 mm²) is coated with about20-220 μg of paclitaxel. Examples of particularly preferred coating fora 6×20 mm vascular stent having an abluminal surface area of about 73mm², and a compressed diameter of about 7 F are listed in Table 5 below.Preferred spray solutions for obtaining durable coating are also listedin Table 5, along with the preferred resulting minimum ratio ofdihydrate to amorphous solid forms obtained by ultrasonic spray coatingof the preferred solution.

In another aspect of the first embodiment, a coating may include two ormore coating layers each comprising or consisting essentially of ataxane therapeutic agent in one or more solid forms. Preferredmultilayer coatings include an outer layer comprising an amorphous solidform of a taxane therapeutic agent. The outer layer preferably coversthe exposed surface of the underlying coating layer(s). The outer layercan optionally include a mixture of other solid forms of the taxanetherapeutic agent with the amorphous solid form. Multilayer coatings caninclude any number of coating layers beneath the outer coating,including 2, 3, 4, 5, 6, 7, and 8-layer coatings. One preferredtwo-layer coating configuration includes a first layer consistingessentially of a dihydrate paclitaxel solid form, and a second layercomprising an amorphous paclitaxel solid form. The second layer can be amixture of the amorphous and the dihydrate solid forms of paclitaxel.

The coated medical device may also include a taxane therapeutic agent atleast partially contained within the medical device 10 frame material27. The medical device may have pores, holes, wells, slots, grooves, orthe like for containing the therapeutic agent and/or other materialssuch as a polymer (see, e.g., co-pending U.S. patent application Ser.No. 10/870,079, filed Jun. 17, 2004 and incorporated herein byreference). Alternatively, the therapeutic agent and/or polymer may beincorporated into a biodegradable medical device that releases the agentas the device degrades, or the therapeutic agent and/or polymer may beincorporated into or placed on the medical device in any other knownmanner. A medical device containing a therapeutic agent within thedevice itself may also have deposited on the device a therapeutic layer,a polymer layer, a layer containing both a therapeutic agent and apolymer, or any combination of these.

Optionally, a polymer may also be deposited on the surface of themedical device prior to during or after deposition of a therapeuticagent. The polymer may comprise, for example, silane, acrylatepolymer/copolymer, acrylate carboxyl and/or hydroxyl copolymer,polyvinylpyrrolidone/vinylacetate copolymer (PVP/VA), olefin acrylicacid copolymer, ethylene acrylic acid copolymer, epoxy polymer,polyethylene glycol, parylene or a parylene derivative, polyethyleneoxide, polyvinylpyridine copolymers, polyamide polymers/copolymerspolyimide polymers/copolymers, ethylene vinylacetate copolymer and/orpolyether sulfones. the polymer(s) may be mixed with or in a separatelayer(s) from the therapeutic agent.

Solid Forms of Taxane Therapeutic Agent Compositions

The different solid forms of the taxane therapeutic agent preferablycontain one or more types of taxane molecules sharing a common coretaxane structure. The core taxane structure can be identified from anultraviolet (UV) spectrum of the taxane therapeutic agent in anysuitable elution medium that permits measurement of a characteristicpeak of the taxane therapeutic agent in solution. Methanol and ethanolare preferred examples of suitable solvents. FIG. 2 shows an ultraviolet(UV) spectrum 100 (Agilent In-line UV Spectrophotometer) of paclitaxelin ethanol, obtained from a 25.67 μM solution of paclitaxel in ethanol.Paclitaxel provides a characteristic peak at 227 nm (102) indicative ofthe presence of the core taxane structure of paclitaxel in the solution.Taxane therapeutic agent in solution can be identified from a UVspectrum of the elution medium comprising the characteristic peak atabout 227 nm, which can be correlated to the presence of the taxanetherapeutic agent in the solution, regardless of the solid form fromwhich the taxane molecule originated.

A first embodiment provides compositions comprising one or more taxanetherapeutic agents in one or more solid forms. Preferably, the taxanesolid forms are selected from the group consisting of: amorphous taxanetherapeutic agent, anhydrous taxane therapeutic agent and dihydratetherapeutic agent. The taxane therapeutic agent is preferablypaclitaxel. Solid forms of taxane therapeutic agents in medical devicecoatings can have identical molecular structures, but differ in thearrangement of the taxane molecules in the coating. Various solid formsof the taxane therapeutic agent can be identified and differentiated onthe basis of one or more physical properties including melting point,solubility and appearance. In addition, various other analytical methodscan be used to identify different solid forms of the taxane therapeuticagents, including vibrational spectroscopy (e.g., Raman or InfraredSpectra), solubilities, melting points, X-ray Diffraction (XRD), ¹³CNuclear Magnetic Resonance (NMR), and Temperature Programmed Desorption(TPD)).

Three different solid forms of the taxane therapeutic agent (amorphous,anhydrous or dihydrate) can be formed by dissolving the solid taxanetherapeutic agent, typically obtained in the anhydrous form, indifferent solvents, as described below. These three solid forms ofpaclitaxel can be prepared and identified by the methods described in J.H. Lee et al, “Preparation and Characterization of Solvent InducedDihydrated, Anhydrous and Amorphous Paclitaxel,” Bull. Korean Chem.Soc., v. 22, no. 8, pp. 925-928 (2001), which is incorporated herein byreference in its entirety.

In a first aspect of the first embodiment, the composition comprises anamorphous taxane therapeutic agent, such as amorphous paclitaxel(“aPTX”). Bulk amorphous paclitaxel can be prepared by dissolving thetaxane therapeutic agent in any suitable aprotic organic solvent,preferably in methylene chloride (dichloromethane), followed by removalof the solvent to leave an amorphous solid. Chloroform can also be usedas the organic solvent. For example, amorphous taxane therapeutic agentcan be formed by first dissolving the solid taxane therapeutic agent indichloromethane, followed by crystallization at and evaporation of thedichloromethane and subsequent vacuum drying of the sample. Desirably,the synthesis method is carried out in a low humidity environment(preferably below about 40% relative humidity, more preferably belowabout 30% and most preferably below about 20% relative humidity orless), and at about 23° C. FIG. 3A shows an infrared vibrationalspectrum of an amorphous paclitaxel prepared according the method ofExample 1. The spectrum of amorphous paclitaxel 100 includes a singlebroad peak at about 1723 cm⁻¹ (102), as well as the following othercharacteristic peaks: 3064 cm⁻¹ (104), 3029 cm⁻¹ (106), 2942 cm⁻¹ (108),1650 cm⁻¹ (110), and 1517 cm⁻¹ (112). The melting points of theamorphous paclitaxel samples prepared according to Example 1 were about190° C.-210° C. An amorphous taxane therapeutic agent can be identifiedby the presence of a single broad peak between about 1700-1740 cm⁻¹ inthe infrared spectrum, typically at about 1723 cm⁻¹. The amorphoustaxane therapeutic agent was found to be more soluble in porcine serumthan the dihydrate taxane therapeutic agent, but less soluble than theanhydrous taxane therapeutic agent.

In a second aspect of the first embodiment, the composition comprises asolvated taxane therapeutic agent, such as dihydrate paclitaxel(“dPTX”). Bulk samples of dihydrate paclitaxel can be prepared bydissolving the taxane therapeutic agent in any suitable alcohol-basedsolvent, followed by evaporation of the solvent to leave a crystallinesolid. Typically, the taxane therapeutic agent is first dissolved in amethanol solvent, followed by the gradual addition of water to thesolution. Dihydrate taxane therapeutic agent is preferably formed by amulti-step process: (1) first, dissolving a solid anhydrous taxanetherapeutic agent in methanol to form a solution, followed by (2) addingwater to the solution in a step-wise manner, followed by (3)crystallization. The water is preferably added very slowly, in adrop-by-drop manner, waiting for solution to become clear before theaddition of the next drop of water, until the solution includes 80% v/vmethanol and 20% v/v water. The dihydrate taxane therapeutic agent canbe collected by filtration and vacuum evaporation of the methanol andwater. Desirably, the synthesis method is carried out in a high humidityenvironment (preferably at least about 20% relative humidity, morepreferably about 40% or greater relative humidity), and at temperaturesof about 23° C., or higher. Alternatively, studies have reportedformation of paclitaxel dihydrate by incubation of anhydrous paclitaxelin water for 24 hours at 25° C. See, e.g., R. T. Liggins et al.,“Solid-State Characterization of Paclitaxel,” Journal of PharmaceuticalSciences, v. 86, No. 12, p. 1461 (December 1997). The dihydratepaclitaxel prepared according to Example 1 was characterized by InfraredSpectrophotometry. FIG. 3B shows an infrared vibrational spectrum of andihydrate paclitaxel prepared according the method of Example 1. Thespectrum of dihydrate paclitaxel 200 includes three or more peaksbetween about 1700-1740 cm⁻¹, typically three peaks at about 1705 cm⁻¹(204), about 1716 cm⁻¹ (203) and about 1731 cm⁻¹ (202), as well as thefollowing other characteristic peaks: 3067 cm⁻¹ (210), 3017 cm⁻¹ (212),2963 cm⁻¹ (214), 1639 cm⁻¹ (206), and 1532 cm⁻¹ (208). The meltingpoints of the dihydrate paclitaxel samples prepared according to Example1 were about 209° C.-215° C. Dehydration of dihydrate paclitaxel hasbeen reported during heating at a rate of 10° C./min over a temperaturerange of between about 35° C. and about 100° C. measured by DSC (withpeaks observed at about 50° C. and about 72° C.), and between about 25°C. and about 85° C. measured by Thermogravimetric Analysis (TGA), withlower temperatures reported at slower heating rates. R. T. Liggins etal., “Solid-State Characterization of Paclitaxel,” Journal ofPharmaceutical Sciences, v. 86, No. 12, pp. 1458-1463, 1461 (December1997) (“Liggins”). The dihydrate paclitaxel has been reported to notshow weight loss or evidence of dehydration when stored for severalweeks when stored at 25° C. at 200 torr. Liggens et al., page 1461.

In a third aspect of the first embodiment, the composition comprises ananhydrous taxane therapeutic agent, such as anhydrous paclitaxel.Anhydrous taxane therapeutic agents preferably contain less than about1.00% water (more preferably less than about 0.60%, 0.55% or 0.50%water), as measured by Karl Fischer analysis. Bulk samples of anhydroustaxane therapeutic agent can be prepared by dissolving a taxanetherapeutic agent such as paclitaxel in any suitable alcohol-basedsolvent, followed by evaporation of the solvent to leave an anhydroussolid. Typically, the taxane therapeutic agent is first dissolved in amethanol solvent, followed by the gradual addition of hexane to thesolution. For example, as described in more detail in Example 1,anhydrous taxane therapeutic agent can be formed by first dissolvingpaclitaxel in methanol to form a solution, followed by addition ofhexane to the solution and subsequent evaporation of the methanol andhexane. Acetone, ethyl acetate or diethyl ether are also suitablesolvents for combination with hexane in forming the anhydrous solid formof a taxane therapeutic agent. The dihydrate paclitaxel preparedaccording to Example 1 was characterized by Infrared Spectrophotometry.FIG. 3C shows an infrared vibrational spectrum of a anhydrous paclitaxelprepared according the method of Example 1. The spectrum of anhydrouspaclitaxel 300 includes a pair of peaks between about 1700-1740 cm⁻¹,typically two peaks at about 1714 cm⁻¹ (302) and about 1732 cm⁻¹ (304),as well as the following other characteristic peaks: 3065 cm⁻¹ (308),2944 cm⁻¹ (310), 1646 cm⁻¹ (306), and 1514 cm⁻¹ (312). The meltingpoints of the anhydrous paclitaxel samples prepared according to Example1 were about 220° C.-221° C. The anhydrous taxane therapeutic agent wasfound to be more soluble in porcine serum than the amorphous taxanetherapeutic agent, and significantly more soluble than the dihydratetaxane therapeutic agent.

Suitable solvent systems for the synthesis of amorphous, dihydrate andanhydrous taxane therapeutic solid forms, as well as characteristicmelting point ranges and infrared spectrum peaks useful in identifyingeach solid form, are provided in Table 1. Other solvent systems can alsobe used to form one or more of the taxane solid forms described herein,and other IR peaks can be used to identify the type(s) of solid formspresent in a taxane therapeutic agent solid sample.

TABLE 1 Preparation and Identification of Taxane Solid Forms DesiredTaxane Solid Form Amorphous Dihydrate Anhydrous Solvent: DichloromethaneMethanol/Water Methanol/ Hexane Melting Point: 190-210° C. 209-215° C.220-221° C. Characteristic Single peak Three or more Two peaks IR peaks:between 1700- peaks between between 1700- 1740 cm⁻¹ 1700-1740 cm⁻¹ 1740cm⁻¹ 3064 cm⁻¹ (104), 3067 cm⁻¹ (210), 3065 cm⁻¹ (308), 3029 cm⁻¹ (106),3017 cm⁻¹ (212), 2944 cm⁻¹ (310) 2942 cm⁻¹ (108) 2963 cm⁻¹ (214) 1650cm⁻¹ (110) 1639 cm⁻¹ (206) 1646 cm⁻¹ (306) 1517 cm⁻¹ (112) 1532 cm⁻¹(208) 1514 cm⁻¹ (312)

Differentiation of taxane solid states by vibrational spectroscopy canalso be performed using Raman scattering. Raman scattering describes thephenomenon whereby incident light scattered by a molecule is shifted inwavelength from the incident wavelength. The magnitude of the wavelengthshift depends on the vibrational motions the molecule is capable ofundergoing, and this wavelength shift provides a sensitive measure ofmolecular structure. That portion of the scattered radiation havingshorter wavelengths than the incident light is referred to asanti-Stokes scattering, and the scattered light having wavelengthslonger than the incident beam as Stokes scattering. Raman scattering isa spectroscopic method useful for the detection of coatings, as theRaman spectra of different coatings or coating layers can be moredistinct than the spectra obtained by direct light absorption orreflectance. FIG. 4A shows an overlay of three Raman spectral traces 400recorded as an average of 10 spectra of three solid paclitaxel coatingson a stainless steel surface using a FT-Raman spectrometer, withexcitation from a 532 nm laser with a power output of 8 mW. The threespectral traces correspond to the dihydrate (402), anhydrous (412) andamorphous (422) paclitaxel samples. Each spectral trace was collectedover a 10 second integration each (total acquisition time of 100seconds), using an air objective (100×, NA=0.9). Differences in thecharacteristic vibrational peaks can be used to differentiate thedihydrate, anhydrous and amorphous forms of the solid paclitaxel. Thecharacteristic vibrational peaks correspond to the infraredcharacteristic peaks discussed with respect to the infrared spectra ofFIGS. 3A-3C, and include the peaks listed in Table 1. Most notably, thepresence of a single peak between 1700-1740 cm⁻¹ indicates the presenceof an amorphous taxane therapeutic agent solid form, the presence ofthree or more peaks between 1700-1740 cm⁻¹ indicates the presence of thedihydrate taxane therapeutic agent solid form, and the presence of twopeaks between 1700-1740 cm⁻¹ indicates the presence of the anhydroustaxane therapeutic agent solid form.

Confocal Raman microscopy allows improved axial and lateral spatialresolution and fluorescence rejection over conventional Ramanmicroscopy. Confocal Raman microscopy can be applied to revealcompositional or structural gradients as a function of depth within asample. A depth profile of a coating can be obtained by confocal Ramanmicroscopy by plotting the intensity of a component-specific vibrationalband as a function of the distance from the sample surface. FIG. 4Bshows a depth profile 500 of a coating comprising a mixture of dihydrateand amorphous solid forms of paclitaxel. The depth profile 500 wasobtained by confocal Raman microscopy, by spatially detecting andplotting the intensity of scattered light matching a first spectrum 512obtained from a dihydrate paclitaxel sample in a first color 502,followed by similarly detecting and plotting the intensity of scatteredlight matching a second spectrum 514 obtained from an amorphouspaclitaxel sample. The depth profile 500 indicates that the dihydratepaclitaxel 502 is largely localized on the surface of the coating whilethe amorphous paclitaxel is predominantly distributed in a layer 504below the dihydrate paclitaxel.

Powder X-ray Diffraction (XRPD) can also be used to differentiatevarious solid forms of taxane therapeutic agents. FIG. 5A shows the XRPDpatterns 600 for amorphous 610 and dihydrate 620 solid forms ofpaclitaxel, with corresponding selected d-spacings of selected peaksprovided in Table 2. Notably, the dihydrate paclitaxel can provide peaksdifferent from the amorphous paclitaxel at 6.1, 9.5, 13.2 and 13.8°2θ(obtained at 25° C.).

TABLE 2 XRPD Selected d-Spacings and Peak Intensities d-spacing °2θ (Å)Anhydrous Dihydrate 6.1 14.5 Strong* 8.8 10.0 Strong* Strong* 9.5 9.3Medium** 10.9 8.11 Medium** 11.1 7.96 Medium** 12.1 7.31 Medium**Strong* 12.3 7.19 Medium** Strong* 13.3 6.65 Medium** 13.8 6.41 Medium**14.1 6.27 Weak*** 19.3 4.59 Weak*** 25.9 3.44 Medium** *= Strong Peak(relative intensity is more than 50); **= Medium Peak (relativeintensity between 20 and 50); ***= Weak Peak (relative intensity lessthan 20)

The data in FIG. 5A and Table 2 was obtained from R. T. Liggins et al.,“Solid-State Characterization of Paclitaxel,” Journal of PharmaceuticalSciences, v. 86, No. 12, pp. 1458-1463 (December 1997), which isincorporated herein by reference. As described by Liggins et al., theanhydrous sample 610 can be obtained by drying paclitaxel (Hauser,Boulder, Colo.) at ambient temperature and reduced pressure (200 torr)in a vacuum oven (Precision Scientific, Chicago, Ill.). Liggins et al.report that the anhydrous sample 610 contained about 0.53% water,measured by Karl-Fischer analysis. The dihydrate sample 620 can beobtained by adding the anhydrous sample above to distilled water andstirring at ambient temperature for 24 hours, followed by filtration andcollection of suspended solid paclitaxel and subsequent drying toconstant weight. Liggins et al. report that the dihydrate sample 620contained about 4.47% water (about 2.22 mol water/mol paclitaxel).Additional details relating to the spectra of FIG. 5A or the data inTable 2 are found in the Liggins et al. reference.

¹³C Nuclear Magnetic Resonance (NMR) can also be used to differentiatevarious solid forms of taxane therapeutic agents. FIG. 5B shows the ¹³CNMR spectra 650 for amorphous 660, anhydrous 670 and dihydrate 680 solidforms of paclitaxel. The data in FIG. 5B was obtained from Jeong HoonLee et al., “Preparation and Characterization of Solvent InducedDihydrated, Anhydrous and Amorphous Paclitaxel,” Bull. Korean Chem. Soc.v. 22, no. 8, pp. 925-928 (2001), incorporated herein by reference. Asdescribed by Lee et al., the spectra 650 in FIG. 5B can be obtainedusing a cross polarization/magic angle spinning (CP/MAS) ¹³C solid formNMR (Bruker DSX-300, Germany) experiment operating at 75.6 MHz. Standardpulse sequences and phase programs supplied by Bruker with the NMRspectrometer can be used to obtain the spectra 650. For each sample,about 250 mg sample can be spun at about 5 kHz in a 4 mm rotor, andcross polarization can be achieved with contact time of 1 ms. Thisprocess can be followed by data acquisition over 35 ms with high protondecoupling. A three-second relaxation delay can be used. The spectra 650are referenced to adamantane, using glycine as a secondary reference(carbonyl signal of glycine was 176.04 ppm). Referring to FIG. 5B, the¹³C solid form NMR spectrum of the dihydrate paclitaxel 680 showsgreater sharpness and peak splitting than either of the other solidforms of paclitaxel, the spectrum of the anhydrous paclitaxel 670 showsgreater sharpness and peak splitting than the spectrum from amorphouspaclitaxel 660, and the spectrum from amorphous paclitaxel 660 showsless resolution and peak splitting than the spectrum from anhydrouspaclitaxel 670.

The presence of different solid forms of the taxane therapeutic agent ina medical device coating can preferably be identified by contacting thecoating with an elution medium that selectively dissolves one solid formmore readily than a second solid form. In solution with an elutionmedium, such as porcine serum or blood, the presence of the taxanetherapeutic agent can be identified, for example by using ultraviolet(UV) spectroscopy or high pressure liquid chromatography (HPLC).

The composition of a coating comprising a mixture of aPTX and dPTX canbe determined by differential elution of each of the solid forms inseries. One preferred method of determining the composition of a coatingcomprises a destructive testing method, whereby a medical device coatedwith a taxane therapeutic agent is placed in contact with a firstelution media, such as porcine serum, that dissolves one solid form ofthe taxane therapeutic agent at a much faster rate than other solidforms of the taxane therapeutic agent. The presence of the taxanetherapeutic agent can be determined by measuring the absorption of thefirst elution medium at 227 nm, as discussed with respect to FIG. 2. Thestrength of absorption of the taxane therapeutic agent in the firstelution medium can be correlated to the amount of the first solid formof the taxane therapeutic agent in the original coating. Similarly, theamount of absorption in the second elution medium can be correlated tothe amount of the second solid form of the taxane therapeutic agent inthe original coating. In addition, two stents coated in the same mannercan be independently contacted with the first medium or the secondmedium, and the amount of taxane therapeutic agent elution in eachmedium can be compared.

For example, porcine serum can be used as a first elution medium todetermine the amount of aPTX in a coating. The rate constant for aPTX inporcine serum is about 100-times the rate constant for dPTX in porcineserum. Accordingly, when a medical device coated with a mixture of aPTXand dPTX is placed in a stream of flowing porcine serum, aPTX will elutemore rapidly than dPTX, and the downstream absorption of paclitaxel inthe elution stream can be correlated to the amount of aPTX in theoriginal coating. Similarly, SDS can subsequently be used as a secondelution medium, to rapidly elute the remaining dPTX from the medicaldevice coating. Measuring the amount of paclitaxel in the SDS stream byabsorption at 227 nm can be correlated to the amount of dPTX in theoriginal coating.

Preferably, the coated medical device can be contacted with a modifiedporcine serum elution medium at a constant flow rate of 16 mL/min for adesired period of time (e.g., 6-24 hours) sufficient to elute the aPTXpresent on the stent. The percentage of the taxane therapeutic agentdissolved can be measured as a function of time by monitoring theoptical density of the first elution medium at 227 nm after contactingthe coated stent, as described above. The modified porcine serum elutionmedium can be prepared by adding 0.104 mL of a 6.0 g/L Heparin solutionto porcine serum at 37° C. and adjusting the pH to 5.6 +/− 0.3 using a20% v/v aqueous solution of acetic acid. The elution rate profile of thetaxane therapeutic agent can be measured for any desired period, andcorrelated to the amount of aPTX in the coating. Subsequently, thecoated medical device is contacted with a second elution mediumcomprising 0.3% sodium dodecyl sulfate (SDS) at 25° C. a constant flowrate of 16 mL/min for a suitable time period to elute the dPTX presentin the coating. The elution rate profile of the taxane therapeutic agentcan be measured for any desired period, and correlated to the amount ofaPTX in the coating.

Methods of Manufacturing Taxane Therapeutic Agent Coatings

A third embodiment provides methods of coating implantable medicaldevices (“medical devices”) with the taxane therapeutic agents in one ormore solid forms. Medical device coatings can comprise one or more ofthe solid forms of the taxane therapeutic agents described with respectto the first embodiment, formed by coating a taxane therapeutic agentspray coating solution in any suitable manner. For example, taxanetherapeutic agents are preferably combined with a solvent to form asolution that can be applied to a surface of a medical device byspraying the solution onto the surface(s).

Taxane Therapeutic Agent Spray Coating Solutions

Spray coating methods are preferably used to deposit taxane therapeuticagents onto the surface(s) of a medical device in one or more differentsolid forms. The spray coating can be performed by any suitable coatingtechnique, but typically includes the step of dissolving the taxanetherapeutic agent in a suitable solvent and spraying the resultingsolution onto the surface of the medical device. Changing the solvent(s)in the solution can change the solid forms of the resulting taxanetherapeutic agent deposited on a medical device. To deposit a coating ofa dihydrate taxane therapeutic agent, a recrystallized dihydrate taxanetherapeutic agent from the first embodiment can be dissolved in asuitable organic alcohol solvent, such as methanol. To deposit a coatinglayer comprising a mixture of dihydrate and amorphous taxane solidforms, the taxane is preferably dissolved in a spray solvent comprisinga mixture of water and a protic solvent such as methanol. Importantly,varying the ratio of water to methanol and/or the concentration of thetaxane in the spray solvent comprising the taxane typically changes thecomposition of the resulting coating layer that is spray deposited.Generally, increasing the amount of methanol in the spray solutionresults in a coating layer with a higher proportion of amorphous taxane.

Importantly, the ratio of amorphous to dihydrate solid forms in a solidtaxane solid coating may be changed by altering the methanol to waterratio and/or the concentration of the taxane therapeutic agent in thespray solution. Decreasing the concentration of the taxane in the spraysolution may require a lower methanol to water ratio (i.e., lessmethanol and more water by volume) to obtain a given dihydrate toamorphous ratio in the solid coating formed after spraying andevaporation of the solvent. The spray solution can be made with anysuitable concentration of the taxane therapeutic agent, althoughconcentrations of about 0.5-5 mM are preferred, with concentrations ofabout 4.68 mM, 2.34 mM, 1.17 mM or 0.70 mM being particularly preferred.The relationship between the concentration of the taxane therapeuticagent in the spray solution, the ratio of methanol to water in the spraysolution and the ratio of dihydrate to amorphous solid forms in thesolid coating formed by spray coating the spray solution is illustratedwith respect to paclitaxel in Tables 3a and 3b. Table 3a providespreferred spray solvent compositions for the spray deposition of acoating layer comprising a mixture of dihydrate paclitaxel and amorphouspaclitaxel using a 4.68 mM paclitaxel concentration in the spraysolution. Table 3a shows the ratio of methanol to water in a spraycoating solution comprising about 2.4 mM paclitaxel, and the ratio ofamorphous:dihydrate paclitaxel in a single coating layer deposited on astent surface by spray coating the solutions with the specifiedcompositions. Table 3b shows the ratio of methanol and water in a spraysolution comprising either 2.4 mM paclitaxel and 0.7 mM paclitaxel.

TABLE 3a Spray Coating Solvent Compositions for 4.68 mM PaclitaxelSolution dPTX:aPTX ratio Solvent (% MeOH:H₂0) >90%:<10% 60:40%-90:10%  60:40%-70:30% 92:8%-93.5:6.5% 40:60%-50:50% 93.5:6.5%-94.55.5%   30:70%-40:60% 95:5%-97.5:2.5%

TABLE 3b Spray Coating Solvent Compositions at Lower PaclitaxelConcentrations Solvent dPTX:aPTX ratio (% MeOH:H₂0) [PTX] mM 52:48%88:12% 2.34 42:58% 90:10% 25:75% 93:7%  78:22% 70:30% 0.70 65:35% 75:25%55:45% 80:20%

In addition to selecting an appropriate solvent system, other coatingparameters such as the spraying apparatus, spray rate, and nozzleconfiguration can be selected to provide coatings comprising one or moresolid forms of a taxane therapeutic agent. The coating of the medicaldevice will now be described using three illustrative methods: spray guncoating, electrostatic deposition (ESD), and ultrasonic deposition(USD). However, the medical device may be coated using any suitablemanner.

Pressure Spray Gun Coating

In a first aspect of the third embodiment, medical device coatingscomprising a taxane therapeutic agent are applied to a surface of amedical device using a spray gun. Spray gun coating may be performedwith a spray solution of paclitaxel in ethanol, without using methanolor water in the spray solution. The surface of the medical device can bebare, surface modified, or a primer coating previously applied to themedical device. Preferably, the coating applied to the surface consistsessentially of the taxane therapeutic agent, and is substantially freeof polymers or other materials. The taxane therapeutic agents describedwith respect to the first embodiment above can be dissolved in asolvent(s) and sprayed onto the medical device under a fume hood using aconventional spray gun, such as a spray gun manufactured by Badger(Model No. 200), or a 780 series spray dispense valve (EFD, EastProvidence, R.I.).

Alignment of the spray gun and stent may be achieved with the use of alaser beam, which may be used as a guide when passing the spray gun overthe medical device(s) being coated. For spray gun coating, thetherapeutic agent is preferably paclitaxel and the solvent is preferablyethanol. Desirably, a solution of about 0.5-5 mM paclitaxel in ethanolis used. More desirably, a solution of about 1-3 mM paclitaxel inethanol is used. Even more desirably, a solution of about 2.4-4.7 mMpaclitaxel in ethanol is used. Other therapeutic agents and solvents mayalso be used in the present invention. The distance between the spraynozzle and the nozzle size can be selected depending on parametersapparent to one of ordinary skill in the art, including the area beingcoated, the desired thickness of the coating and the rate of deposition.Any suitable distance and nozzle size can be selected. For example, forcoating an 80 mm long stent, a distance of between about 1-7 inchesbetween the nozzle and stent is preferred, depending on the size of thespray pattern desired. The nozzle diameter can be, for example, betweenabout 0.014-inch to about 0.046-inch.

Varying parameters in the spray coating process can result in differentsolid forms of the taxane therapeutic agent in a deposited coating.Spray coating parameters such as solvent system, fluid pressure (i.e.,tank pressure), atomization pressure, ambient temperature and humidity.The solvent is desirably volatile enough to be readily removed from thecoating during or after the spray coating process, and is preferablyselected from the solvents discussed with respect to the firstembodiment for each solid form of a taxane therapeutic agent.

Typically, spray coating in lower humidity, higher atomization pressureand/or lower temperature (e.g., room temperature) conditions, favor theformation of the amorphous solid form of the taxane therapeutic agent.Methods of coating amorphous taxane therapeutic agents using a 780S-SSspray dispense valve (EFD, East Providence, R.I.) can comprise the stepsof: dissolving solid paclitaxel in ethanol to form a spray solution of adesired concentration (e.g. 4.68 mM), and spraying the solution onto amedical device with an atomization pressure of about 5-10 psi in anenvironment having a relative humidity of 30% or lower. Preferably, thespraying step is performed at a temperature of between about 65° F. and75° F., and with a fluid pressure of between about 1.00 and 5.00 psi.For example, amorphous paclitaxel (aPTX) coatings have been depositedusing the EFD 780S-SS spray valve (EFD, East Providence, R.I.) under thefollowing conditions: (1) 4.0 g/L PTX (4.68 mM) in ethanol spraysolution, 20% relative humidity, 13.00 psi atomization pressure, 2.00psi fluid (tank) pressure and 80° F. ambient temperature; and (2) 4.0g/L PTX in ethanol spray solution, 30% relative humidity, 25.00 psiatomization pressure, 1.50 psi fluid (tank) pressure and 75° F. ambienttemperature. An amorphous taxane therapeutic agent coating has a clearor transparent appearance.

Spray coating in higher humidity, lower atomization pressure and/orhigher temperature conditions, favor the formation of the dihydratesolid form of the taxane therapeutic agent. Methods of coating dihydratetaxane therapeutic agents are provided which comprise the steps of:dissolving solid paclitaxel in ethanol to form a solution, and sprayingthe solution onto a medical device. When spray coating with the EFD780S-SS spray valve (EFD, East Providence, R.I.), the spraying step ispreferably performed at a temperature of 75° F. or greater, and with afluid pressure of between about 1.00 and 5.00 psi. For example,dihydrate paclitaxel (dPTX) coatings have been deposited using an EFD780S-SS spray valve (EFD, East Providence, R.I.) under the followingconditions: (1) 4.0 g/L PTX in ethanol spray solution, 44% relativehumidity, 12.00 psi atomization pressure, 2.50 psi fluid (tank) pressureand 80° F. ambient temperature; or (2) 4.0 g/L PTX in ethanol spraysolution, 55% relative humidity, 5.00 psi atomization pressure, 1.00 psifluid (tank) pressure and 70° F. ambient temperature.

Electrostatic Spray Coating

In a second aspect of the third embodiment, the taxane therapeutic agentis dissolved in a suitable solvent or combination of solvents and thensprayed onto the medical device using an electrostatic spray deposition(ESD) process. The ESD process generally operates on the principle thata charged particle is attracted towards a grounded target. One typicalESD process may be described as follows. The solution that is to bespray coated is typically charged to several thousand volts (typicallynegative) and the medical device surface held at ground potential. Thecharge of the spray solution is generally great enough to cause thesolution to jump across an air gap of several inches before landing onthe surface. As the spray solution is in transit towards the surface,the spray fans out in a conical pattern, promoting formation of a moreuniform coating. In addition to the conical spray shape, electrons arefurther attracted towards the conducting portions of the surface, ratherthan towards the non-conductive base the medical device surface ismounted on, leaving the coating mainly on the surface only.

During the ESD spray coating process, the spray solution is forcedthrough a capillary subjected to an electrical field. The spray solutionleaves the capillary in the form of a fine spray, the shape of which isdetermined by the electrical field. The medical device is then coated byplacing it in the spray and allowing the solvent to evaporate, leavingthe desired coating on the surface of the device.

The ESD method allows for control of the coating composition and surfacemorphology of the deposited coating. In particular, the morphology ofthe deposited coating may be controlled by appropriate selection of theESD parameters, as set forth in WO 03/006180 (Electrostatic SprayDeposition (ESD) of biocompatible coatings on Metallic Substrates), thecontents of which are incorporated by reference. For example, a coatinghaving a uniform thickness and grain size, as well as a smooth surface,may be obtained by controlling deposition conditions such as depositiontemperature, spraying rate, precursor solution, and bias voltage betweenthe spray nozzle and the medical device being coated. The ESD spraysolution preferably includes methanol. It is believed that the additionof methanol increases the polarity of the solvent solution, therebyproviding a fine spray that is ideal for use in an electrostatic coatingprocess. For example, the spray solution can comprise about 50-80%methanol (by volume), more desirably about 65-75% methanol and mostpreferably up to about 70% methanol.

Ultrasonic Spray Coating

In a third and most preferred aspect of the third embodiment, the taxanetherapeutic agent is spray coated onto a medical device surface using anultrasonic spray deposition (USD) process. Ultrasonic nozzles employhigh frequency sound waves generated by piezoelectric transducers whichconvert electrical energy into mechanical energy. The transducersreceive a high frequency electrical input and convert this intovibratory motion at the same frequency. This motion is amplified toincrease the vibration amplitude at an atomizing surface.

Ultrasonic nozzles are typically configured such that excitation of apiezoelectric crystals creates a longitudinal standing wave along thelength of the nozzle. The ultrasonic energy originating from thetransducers may undergo a step transition and amplification as thestanding wave traverses the length of the nozzle. The nozzle istypically designed such that a nodal plane is located between thetransducers. For ultrasonic energy to be effective for atomization, thenozzle tip must be located at an anti-node, where the vibrationamplitude is greatest. To accomplish this, the nozzle's length should bea multiple of a half-wavelength. In general, high frequency nozzles aresmaller, create smaller drops, and consequently have smaller maximumflow capacity than nozzles that operate at lower frequencies.

Liquid introduced onto the atomizing surface absorbs some of thevibrational energy, setting up wave motion in the liquid on the surface.For the liquid to atomize, the vibrational amplitude of the atomizingsurface should be adequately controlled. Below a certain amplitude, theenergy may be insufficient to produce atomized drops. If the amplitudeis excessively high, cavitation may occur. The input power is preferablyselected to provide an amplitude producing a desired spray having afine, low velocity mist. Since the atomization mechanism relies largelyon liquid being introduced onto the atomizing surface, the rate at whichliquid is atomized depends on the rate at which it is delivered to thesurface.

For example, the medical device may be coated using an ultrasonic spraynozzle, such as those available from Sono-Tek Corp., Milton, N.Y. Thespray solution can be loaded into a syringe, which is mounted onto asyringe pump and connected to a tube that carries the solution to theultrasonic nozzle. The syringe pump may then used to purge the air fromthe solution line and prime the line and spay nozzle with the solution.The stent may be loaded onto a stainless steel mandrel in the ultrasoniccoating chamber. The stent may optionally be retained around a mandrelduring coating. Alternatively, the stent may be secured and rotated on aclip or in within a steam of rapidly flowing gas such as nitrogen.Preferably, contact between the stent and the mandrel is minimized so asto prevent a “webbed” coating between struts. Typically, the luminalsurface is not coated although the coating may be applied to anysurface, if desired.

The medical device may be a vascular stent mounted around a mandrel. Themandrel may be fastened onto a motor, positioned below the ultrasonicnozzle. The motor rotates the mandrel at a pre-set speed andtranslationally moves the stent underneath the ultrasonic spray. In oneaspect, the rotational speed is set to 10 rpm and the translationalspeed is set to 0.01 mm per second. In another aspect, the rotationalspeed is set to 60 rpm and the translational speed is set to 0.05 mm persecond. In yet another embodiment, the rotational speed is set to30-150, preferably about 110 rpm, and the translational speed is set to0.19 mm per second. Other speeds and combinations may also be used inthe present invention. Preferred coating parameters for USD using aSono-tek Model 06-04372 ultrasonic nozzle are provided in Table 4 below:

TABLE 4 Ultrasonic Spray Deposition Parameters for Sono-tek Model06-04372 Flow Coating Rotation Nozzle Process rate velocity Speed PowerGas Distance (mL/min) (in/sec) (rpm) (watts) (psi) (mm) 0.01-2 0.01-0.530-150 0.9-1.2 0.1-2.5 1-25

Importantly, ultrasonic spray coating is preferably performed at anambient temperature of about 85-87° F. and in a coating chamber at apressure of less than about 0.05 psi. The temperature is preferablyselected to provide a desirably uniform, solvent-free coating.Preferably, the coating is performed at a temperature of about 60-90°F., preferably about 85-87° F. The quality of the coating may becompromised if coating is performed outside the preferred temperaturerange. The temperature during ultrasonic spray coating should be highenough to rapidly evaporate the methanol in the spray solution beforecontacting the stent (i.e., at least about 80 F.).

Most preferably, the ultrasonic spray coating is performed at a flowrate of about 0.03 mL/min, a coating velocity of about 0.025 in/sec, arotation speed of about 60 rpm, a nozzle power of about 1 watt, aprocess gas pressure of about 2 psi, a distance of about 12 mm betweenthe nozzle and medical device, and a temperature of about 85° F. withina coating chamber. The coating chamber is purged with nitrogen todisplace oxygen in the system. During the process, the stent is kept atambient temperature and in a closed chamber.

Taxane coatings desirably comprise at least one layer comprising adurable amorphous solid form. Preferably, coatings comprising a mixtureof amorphous and dihydrate taxane solid forms preferably include aminimum amount of amorphous taxane to impart a desired level ofdurability to the coating. Typically, coatings with at least about25-30% dihydrate taxane (i.e., dPTX:aPTX ratio including about 70-75%dPTX) have a desired level of durability to withstand a stent crimpingprocedure. Preferred spray solution compositions are selected to providea coating having a taxane therapeutic agent with a dihydrate:amorphoussolid form ratio with desired properties of elution rate, surfaceuniformity and durability. For example, preferred solvent systems forultrasonic spray coating include a dihydrate:amorphous paclitaxelcoating (e.g., from a SonoTek 06-04372 ultrasonic nozzle) with 60-70% wdihydrate (remainder amorphous) paclitaxel, and may be prepared byselecting paclitaxel, methanol and water concentrations according toTables 3a-3b while spray coating at about 84-87 F. within the parametersspecified in Table 4 above. The coatings can also be applied (in totalor in part) by a coating method described with respect to the thirdembodiment, or any other suitable manner. For example, the coating mayalso be deposited onto the medical device by spraying, dipping, pouring,pumping, brushing, wiping, vacuum deposition, vapor deposition, plasmadeposition, electrostatic deposition, epitaxial growth, or any othermethod known to those skilled in the art. Preferably, however, themedical device coatings are applied by spraying methods, such as thosedescribed with respect to the third embodiment above.

Modification of Medical Device Surface to Promote Adhesion of Coating

Optionally, prior to spray coating of the taxane therapeutic agent, thesurface of the medical device can be prepared to promote adhesion of thecoating material before depositing the coating. Useful methods ofsurface preparation can include, but are not limited to cleaning;physical modifications such as etching, drilling, cutting, or abrasion;and chemical modifications such as solvent treatment, the application ofprimer coatings, the application of surfactants, plasma treatment, ionbombardment, covalent bonding and electrochemical methods such aselectropolishing, striking, electroplating and electrochemicaldeposition. Such surface preparation may serve to activate the surfaceand promote the deposition or adhesion of the coating on the surface.Surface preparation can also selectively alter the release rate of thetaxane therapeutic agent. Any additional coating layers can similarly beprocessed to promote the deposition or adhesion of another layer, tofurther control the release of the taxane therapeutic agent, or tootherwise improve the biocompatibility of the surface of the layers. Forexample, plasma treating an additional coating layer before depositing ataxane therapeutic agent thereon may improve the adhesion of the taxanetherapeutic agent, increase the amount of taxane therapeutic agent thatcan be deposited, and allow the taxane therapeutic agent to be depositedin a more uniform layer.

Sterilization of Medical Devices

The medical devices of the present invention can be sterilized prior toimplantation into the body, including before and/or after coating.Preferably, the coated medical device is sterilized using a conventionalchemical vapor sterilization process that does not undesirably degradeor alter the taxane therapeutic coating. For example, a conventionalethylene oxide (ETO) sterilization process may be used, which mayinvolve exposing the coated medical device to ETO gas at a temperatureof about 120 F. for a period of about 1-3 hours. Since ethylene oxidegas readily diffuses through many common packaging materials and iseffective in killing microorganisms at temperatures well below thoserequired for heat sterilization techniques, ETO sterilization can permitefficient sterilization of many items, particularly those made ofthermoplastic materials, which cannot withstand heat sterilization. Theprocess generally involves placing an item in a chamber and subjectingit to ethylene oxide vapor. When used properly, ethylene oxide is notonly lethal to microorganisms, but it is also non-corrosive, readilyremoved by aeration.

Notably, the ratio of dihydrate to amorphous solid forms of the taxanetherapeutic agent may increase during ETO sterilization. For example,increases of up to about 5% in the proportion of dihydrate paclitaxelwere observed in coatings consisting of paclitaxel in both the dihydrateand amorphous solid forms prior to sterilization. Typically, coatedmedical devices can be sterilized within suitable packaging, such as abag, pouch, tube or mold.

Alternatively, the medical device may be loaded into final packaging,and gamma irradiated in a gamma chamber. In one embodiment, theimplantable medical device is irradiated with between 1 and 100 kGy. Inanother embodiment, the implantable medical device is irradiated withbetween 5 and 50 kGy, and in yet another embodiment, the implantablemedical device is irradiated with between 25 and 28 kGy.

Therapeutic Agent Elution Profile

Local administration of therapeutic agents may be more effective whencarried out over an extended period of time, such as a time period atleast matching the normal reaction time of the body to an angioplastyprocedure, for example. At the same time, it may be desirable to providean initial high dose of the therapeutic agent over an initial period.For example, local administration of a therapeutic agent over a periodof days or even months may be most effective in treating or inhibitingconditions such as restenosis. The coating may be configured to providea delayed release of the taxane therapeutic agent when the medicaldevice is implanted, permitting the coatings to be configured to providefor the coated taxane therapeutic agent(s) to be released for desirableperiods of time. For example, a coating consisting essentially of thetaxane therapeutic agent in one or more solid forms can be configured torelease less than 90 percent of the coated taxane therapeutic agent intoan aqueous environment (such as blood or porcine serum) over a period ofat least about 6 months, two months, one month, one week, or one day. Inparticular, a coating can have an outer layer of more than 50%rapidly-dissolving amorphous paclitaxel over a layer of more than 50%slow-dissolving dihydrate paclitaxel.

The release characteristics of a coated taxane therapeutic agent can bedescribed by an elution profile. The elution profile of a medical devicecomprising a taxane therapeutic agent shows the percentage of the taxanetherapeutic agent that dissolves as a function of time in a givenelution medium. The rate of dissolution of the taxane therapeutic agentcan vary based on the elution medium being used and the solid form ofthe taxane therapeutic agent before dissolution. An elution profile canbe obtained by any suitable method that allows for measurement of therelease of the taxane therapeutic agent from the coating in a mannerthat can be measured with a desired level of accuracy and precision. Inone embodiment, the elution profile of the release of a taxanetherapeutic agent is obtained by contacting the medical device with asuitable elution medium. The elution medium can be formulated tosimulate conditions present at a particular point of treatment within abody vessel. For example, an elution medium comprising porcine serum canbe used to simulate implantation within a blood vessel. The release oftaxane therapeutic agent from the medical device can be measured by anysuitable spectrographic method, such as measurement of a UV absorptionspectrum of the test fluid after contacting the medical device.Typically, the intensity of absorption at characteristic UV absorptionpeak, such as about 227 nm, can be correlated to the presence and amountof a taxane therapeutic agent in a sample. The amount of taxanetherapeutic agent on the medical device can be determined by contactingthe medical device with a suitable elution medium and detecting theamount of taxane therapeutic agent released from the medical device intothe elution medium.

An elution medium can be selected to solubilize one solid form of ataxane therapeutic agent more rapidly than other solid forms of thetaxane therapeutic agent, while allowing for subsequent measurement ofthe solubilized taxane therapeutic agent in a manner that can becorrelated to the amount of the more soluble solid form of the taxanetherapeutic agent released from the medical device. Subsequently, asecond elution medium can be selected to quickly solubilize one or moreother solid forms of the taxane therapeutic agent that did not dissolvein the first elution medium. Preferably, substantially all the taxanetherapeutic agent of at least one solid form is removed from the medicaldevice after contact with an elution medium for a desired period oftime. The taxane therapeutic agent is subsequently detected in theelution medium. The detection of the taxane therapeutic agent iscorrelated to the amount of a particular solid form of the taxanetherapeutic agent that was present on the medical device surface priorto contacting the medical device with the elution medium.

In one embodiment, the elution profile of a paclitaxel coating on amedical device is determined by first contacting the medical device witha first elution medium that readily dissolves the amorphous paclitaxelat least about 10-times more rapidly than the dihydrate paclitaxel, andthen subsequently detecting the amount of taxane therapeutic agentwithin the elution medium. The medical device is exposed to the firstelution medium and the rate of release of the taxane therapeutic agentfrom the medical device is determined by detecting the taxanetherapeutic agent in the first elution medium for a first desired periodof time. After the first desired period of time, the amount of taxanetherapeutic agent remaining on the medical device can be determined bycontacting the medical device with a second elution medium that readilydissolves the dihydrate paclitaxel, and subsequently detecting theamount of taxane therapeutic agent leaving the medical device in thesecond elution medium.

Any suitable analytical technique(s) may be used to detect a taxanetherapeutic agent in an elution medium. Suitable detection methods, suchas a spectrographic technique, permit measurement of a property of theelution medium that can be correlated to the presence or concentrationof the taxane therapeutic agent with a desired level of accuracy andprecision. In one embodiment, absorption spectroscopy (e.g., UV) can beused to detect the presence of a taxane therapeutic agent, such as in anelution medium. Accordingly, the Beer-Lambert Correlation may be used todetermine the concentration of a taxane therapeutic agent in a solution.This correlation is readily apparent to one of ordinary skill in theart, and involves determining the linear relationship between absorbanceand concentration of an absorbing species (the taxane therapeutic agentin the elution medium). Using a set of standard samples with knownconcentrations, the correlation can be used to measure the absorbance ofthe sample. A plot of concentration versus absorbance can then be usedto determine the concentration of an unknown solution from itsabsorbance. UV absorbance of the taxane therapeutic agent at 227 nm canbe measured (see FIG. 2), and the absorbance at this wave length can becorrelated to concentration of the taxane in the test solution.

FIG. 6A shows elution profiles 700 for two medical devices in porcineserum elution media at 25° C. The first elution profile 710 was obtainedfrom a first coated vascular stent coated with a single layer ofamorphous paclitaxel. The second elution profile 720 was obtained from asecond coated vascular stent coated with a single layer of dihydratepaclitaxel. The amorphous paclitaxel coating on the first vascular stenthad a clear, transparent visual appearance, while the dihydratepaclitaxel coating on the second vascular stent had an opaque, white andcloudy visual appearance. Referring to the first elution profile 710,obtained from the amorphous paclitaxel coating, 100% of the amorphouspaclitaxel dissolved within about 6.5 hours (400 minutes), while lessthan 40% of the second (dihydrate) coating eluted under the sameconditions after about 24 hours.

A preferred first elution medium is an aqueous solution comprising 0.1%to about 10% of a cyclodextrin. In one aspect, an elution profile may beobtained by contacting a coated medical device comprising a taxanetherapeutic agent with an elution medium comprising a cyclodextrin. Acyclodextrin is a cyclic oligosaccharide formed from covalently-linkedglucopyranose rings defining an internal cavity. The diameter of theinternal axial cavity of cyclodextrins increases with the number ofglucopyranose units in the ring. The size of the glucopyranose ring canbe selected to provide an axial cavity selected to match the moleculardimensions of a taxane therapeutic agent. The cyclodextrin is preferablya modified β-cyclodextrin, such asHeptakis-(2,6-di-O-methyl)-β-cyclodextrin (HCD). Suitable cyclodedtrinmolecules include other β-cyclodextrin molecules, as well asγ-cyclodextrin structures.

The elution medium comprising a cyclodextrin can dissolve a taxanetherapeutic agent so as to elute the taxane therapeutic agent from amedical device coating over a desired time interval, typically about 24hours or less (less than comparable elution times in porcine serum).Preferably, the cyclodextrin elution medium is formulated to providedistinguishable elution rates for different coating configurations,providing different elution profiles for different solid forms of ataxane therapeutic agent in the coating, or different types or amountsof polymers incorporated with the taxane therapeutic agent within acoating. The elution medium may be contacted with a medical devicecomprising a taxane therapeutic agent, such as paclitaxel, in any mannerproviding an elution profile indicative of the arrangement of the taxanetherapeutic agent molecules in the coating. For example, the elutionmedium may contact a medical device coating in a continuous flowconfiguration, or in a batch testing configuration.

Taxane therapeutic agents typically have different elution profiles indifferent elution media. FIG. 6B shows elution profiles 725 for thefirst and second vascular stents in a 0.5% w/v aqueous solution ofHeptakis-(2,6-di-O-methyl)-β-cyclodextrin (HCD) elution medium at 25° C.The first elution profile 727 was obtained from the first coatedvascular stent coated with a single layer of amorphous paclitaxel. Thesecond elution profile 729 was obtained from the second coated vascularstent coated with a single layer of dihydrate paclitaxel. Referring tothe first elution profile 727, obtained from the amorphous paclitaxelcoating, about 80% of the amorphous paclitaxel dissolved within about 1hour, while less than 20% of the dihydrate paclitaxel was releasedwithin 1 hour in the second elution profile 729. Accordingly, comparingFIGS. 6A and 6B, both the HCD and porcine serum elution mediaselectively dissolved the amorphous paclitaxel distinguishably morerapidly than the dihydrate paclitaxel, however the HCD elution mediumdissolved the amorphous paclitaxel much more quickly (727) than theporcine serum (710).

FIG. 6C shows elution profiles 730 for six medical devices in porcineserum elution media at 25° C. for 30 days. All six medical devices werecoated with a single layer of paclitaxel in various solid forms, withouta polymer or any release-rate-modifying substance. A first elutionprofile 732, a second elution profile 733 and a third elution profile734 were obtained coated vascular stents coated with a single layer ofabout 1 μg/mm² (±15%) paclitaxel layer with about 70% of the paclitaxelin the less soluble dihydrate solid form and about 30% of the paclitaxelin the more soluble amorphous solid form. Notably, increasing the totalamount of paclitaxel in the single-layer coating from 80 μg in the firstelution profile 732 to 82 μg in the second elution profile 733 to 95 μgin the third elution profile 734 resulted in a steady increase in theelution rate. A third elution profile 736, a fifth elution profile 737and a sixth elution profile 738 were obtained coated vascular stentscoated with a single layer of about 3 μg/mm² (±15%) paclitaxel layerwith about 80% of the paclitaxel in the dihydrate solid form and about20% of the paclitaxel in the amorphous solid form. Again, increasing thetotal amount of paclitaxel in the single-layer coating from 222 μg inthe fourth elution profile 736 to 242 μg in the sixth elution profile738 to 253 μg in the fifth elution profile 737 resulted in a steadyincrease in the elution rate. The rate of elution from the 3 μg/mm²paclitaxel coatings was slower than the rate of elution from the 1μg/mm² coatings because the amount of the paclitaxel in the less solubledihydrate solid form was increased from 70% in the 3 μg/mm² paclitaxelcoatings to 80% in the 1 μg/mm² paclitaxel coatings. Accordingly, therate of release of a paclitaxel coating can be varied by changing theamount of each solid form of the paclitaxel present in a coating. Thus,by varying the solid form of a taxane therapeutic agent, a lower dose ofpaclitaxel can be used to provide a more sustained release than a higherdose of paclitaxel, without introducing a polymer to the coating.

Another suitable elution medium for taxane therapeutic agent is sodiumdodecyl sulfate (SDS). FIG. 7A shows the solubility of amorphouspaclitaxel in sodium dodecyl sulfate (SDS). FIG. 7A is a graph 780showing a first elution profile 782 obtained from a first coatedvascular stent coated with a single layer of amorphous paclitaxel (aPTX)in 0.3% SDS elution medium at 25° C. FIG. 7B shows the solubility ofdihydrate paclitaxel in sodium dodecyl sulfate (SDS). FIG. 7B is a graph790 showing a second elution profile 792 obtained from a second coatedvascular stent coated with a single layer of dihydrate paclitaxel (dPTX)in the same 0.3% SDS elution medium at 25° C. The rate of elution ofamorphous paclitaxel in the first elution profile 782 is more rapid thanthe rate of elution of the dihydrate paclitaxel in the second elutionprofile 792. However, both solid forms of paclitaxel are significantlymore soluble in the 0.3% SDS elution medium than in the porcine serumelution media (e.g., compare FIG. 6A and FIGS. 7A-7B).

FIG. 8A shows a first-order kinetic plot 800 of the data from the firstelution profile 710 in FIG. 6A. The first kinetic plot 800 plots thenatural log of the percent of the amorphous paclitaxel (710) coatingremaining on the first vascular stent as a function of time (minutes)from data obtained for FIG. 6A. The data in the first kinetic plot 800closely fits to straight line 802 (R²=0.9955), indicating that theelution of amorphous paclitaxel in porcine serum at 25° C. follows firstorder kinetics. Based on the slope of the line 802, the first order rateconstant of amorphous paclitaxel in porcine serum (25° C.) is about0.0244 min⁻¹, with a half life of about 30 minutes.

Similarly, FIG. 8B shows a first-order kinetic plot 850 of the data fromthe second elution profile 720 in FIG. 6A. The kinetic plot 850indicates the natural log of the percent of the dihydrate paclitaxel(720) coating remaining on the second vascular stent as a function oftime (minutes). The data in the first kinetic plot 850 also closely fitsto straight line 852 (R²=0.9925), indicating that the elution ofdihydrate paclitaxel in porcine serum at 25° C. also follows first orderkinetics. Based on the slope of the line 852, the first order rateconstant of dihydrate paclitaxel in porcine serum (25° C.) is about0.0003 min⁻¹, with a half life of about 38.5 hours (2,310 minutes).Therefore, the rate of elution of the amorphous paclitaxel is about100-times faster than dihydrate paclitaxel in porcine serum (25° C.).

Based on the first order rate constants obtained for amorphouspaclitaxel (k₁=0.0244 min⁻¹) and for dihydrate paclitaxel (k₂=0.0003min⁻¹) in porcine serum, the rate of dissolution of a coating comprisingof a mixture of amorphous and dihydrate taxane therapeutic agents inporcine serum can be formulated as a function of the proportion of eachsolid form by the formulae: f=1−(ae^(k) ¹ ^(t)+(1−a)e^(k) ² ^(t)) anda=(1−f−e^(k) ² ^(t))/e^(k) ¹ ^(t)−e^(k) ² ^(t), where f is the fractiondissolved, k₁ and k₂ are the rate constants for amorphous and dihydratepaclitaxel respectively, a is the proportion of amorphous taxanetherapeutic agent in the coating layer, (1−a) is the amount of dihydratetaxane therapeutic agent in the coating layer and e is the naturallogarithmic base. FIG. 9 shows a plot of the predicted dissolution ratesof various mixtures of amorphous paclitaxel and dihydrate paclitaxelhaving the first order rate constants k₁ and k₂ (respectively) inporcine serum as a function of time. A first trace 904 corresponds tothe predicted dissolution profile of a coating comprising 10% amorphouspaclitaxel (aPTX) and 90% dihydrate paclitaxel (dPTX). The compositioncorresponding to the traces of FIG. 9 is provided in Table 5 below. Thepercentage of the paclitaxel dissolved as a function of time for about 1week (10,000 minutes) is shown for each trace.

TABLE 5 Compositions of predicted elution profiles shown in FIG. 9 Tracein FIG. 9 Percentage aPTX Percentage dPTX 902 100 0 904 90 10 906 80 20908 70 30 910 60 40 912 50 50 914 40 60 916 30 70 918 20 80 920 10 90922 0 100

Notably, varying the relative amounts of amorphous and dihydratepaclitaxel in the coating can result in wide variation of the rate ofrelease of paclitaxel from the coating. Referring again to FIG. 9, afterabout 1-2 hours (100 minutes), less than 10% of the dihydrate paclitaxelcoating (922) is predicted to be dissolved, while about 80% of theamorphous paclitaxel coating (902) is predicted to be dissolved.Mixtures of amorphous and dihydrate paclitaxel (904-920) can showintermediate amounts of elution. Similarly, after about 16 hours (1,000minutes), less than 30% of the dihydrate paclitaxel coating (922) ispredicted to be dissolved, about 100% of the amorphous paclitaxelcoating (902) is predicted to be dissolved and mixtures of amorphous anddihydrate paclitaxel (904-920) can show intermediate amounts of elution.Finally, after about 1 week (10,000 minutes), about 90-95% of thedihydrate paclitaxel coating (922) is predicted to be dissolved, withmixtures of amorphous and dihydrate paclitaxel (904-920) showing nearly100% elution.

The elution profiles of coatings modeled by the traces of FIG. 9correspond to coatings having a taxane therapeutic agent distributed ina mixture of multiple solid forms within the coating, most preferably acoating formed from a mixture of amorphous state paclitaxel and asolvated (e.g., dihydrate) solid form paclitaxel. A coating having amixture of the amorphous and taxane therapeutic agent solid forms can beprepared as described above with respect to the third embodiment.

The dihydrate paclitaxel taxane therapeutic agent is typically lesssoluble than the amorphous taxane therapeutic agent or the anhydroustaxane therapeutic agent. In porcine serum at 25° C., samples of thedihydrate paclitaxel solid form were about 100-times less soluble thansamples of the anhydrous paclitaxel solid form. Other studies havereported decreased solubility of dihydrate paclitaxel in water at 37° C.compared to anhydrous paclitaxel. Anhydrous paclitaxel is reported witha solubility of about 3.5 μg/mL after about 5 hours in 37° C. water,while dihydrate paclitaxel has a solubility of less than 1.0 μg/mL in37° C. water over the same time period. R. T. Liggins et al.,“Solid-State Characterization of Paclitaxel,” Journal of PharmaceuticalSciences, v. 86, No. 12, 1458-1463 (December 1997).

Coating Durability

The coating compositions preferably comprise a taxane therapeutic agentwith a desired level of durability for an intended use. Coatingsconsisting of dihydrate taxane therapeutic agents demonstrated a lowdurability, and a high propensity for dissociation from the stentcoating upon crimping. In contrast, the amorphous solid form of thetaxane therapeutic agents demonstrated greater durability andsubstantially lower tendency to dissociate from a coated stent uponcrimping of the stent. In aqueous media such as porcine serum and blood,the amorphous taxane therapeutic agent solid form is more soluble thanthe dihydrate taxane therapeutic agent. Therefore, the release rate andthe durability of the coating can be altered by incorporating a desiredamount of dihydrate or amorphous solid forms of the taxane therapeuticagent in one or more coating layers. Preferred coatings comprise one ormore durable layers comprising a suitable amount of an amorphous taxanetherapeutic agent solid form to impart a desired durability to thecoating. For example, the outer layer can comprise at least about 5, 10,15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80%, or more, of an amorphoustaxane therapeutic agent to impart durability to a coating. forsustained release coatings, durability may be balanced with the goal ofextending the elution time by adding more of the slower-elutingdihydrate taxane therapeutic agent.

Coating durability describes the resistance of a coating to loss ofintegrity due to abrasion, bending or mechanical loading throughmechanisms such as flaking, cracking, chipping and the like. Thedurability of a coating can be measured by weighing a coated medicaldevice prior to physical agitation of the coating by a test process suchas crimping, shaking, freezing or abrading the stent, weighing thecoated stent a second time after the test process is performed, andcomparing the second weight to the first weight. For a given physicaltest procedure, coating durability can be quantified by the amount ofweight loss from the first weight to the second weight. Accordingly, thelower the amount of weight loss as a result of performing a physicaltest on the coated medical device, the more durable the coating is. Onepreferred physical test for implantable coated vascular stents is theprocess of crimping the stent from an expanded state (in which the stentis coated), to a radially compressed state for delivery within a bodyvessel. The durability of a radially expandable medical device can bequantified as the percentage weight loss of the coated medical devicebefore and after crimping the medical device.

The difference in weight of a coated stent before and after crimpingprovides one indicator of the coating durability. Highly durablecoatings typically have a lower weight loss during the crimping process.Taxane coatings with a higher proportion of dihydrate are typically lessdurable (i.e., higher weight loss during the crimping process).Preferred taxane coatings exhibit a coating weight loss of less thanabout 10%, more preferably less than about 8%, 6%, 4%, 3%, 2%, 1% or0.5% and most preferably less than about 0.1% before and after crimpingto a diameter of 6 French (6F). The coating weight loss can be measuredby: (1) weighing an uncoated stent in the radially expanded state toobtain a first weight (“weight (1)”), (2) coating the stent in theexpanded condition, (3) weighing the coated stent to obtain a secondweight (“weight (2)”), (4) crimping the coated stent and (5) weighingthe crimped, coated stent to obtain a third weight (“weight (3)”). Thecoating weight loss is: [weight (2)−weight (1)]−[weight (3)−weight (1)],or simply weight (2)−weight (3). Accordingly, one particularly preferredcoating comprises a mixture of amorphous taxane therapeutic agent anddihydrate taxane therapeutic agent. Coatings comprising mixtures of dPTXwith at least about 25-50% aPTX on the outside surface of the coatinghave shown desired durability characteristics. As discussed above withrespect to FIG. 9, increasing the proportion of aPTX increases theelution rate of the coating in porcine serum. Particularly preferredcoatings applied with a 4.68 mM paclitaxel solution comprise about 30%aPTX and 70% dPTX. These preferred ratios change as the concentration ofpaclitaxel in the spray coating solution changes, as discussed above. Astent comprising a 30:70 aPTX:dPTX was coated in a radially expandedstate, crimped to fit a delivery catheter, and re-weighed. For example,a typical 30:70 aPTX:dPTX coated stent lost less than 5% weight as aresult of crimping to a 6 F size.

The durability of the coating may also be evaluated as the resistance todisplacement of the coating in response to mechanical abrasion. Forinstance, scraping a non-durable coating may displace a portion of thecoating from one area to another, resulting in a scratching or pittingof the surface without a net change in the weight of the coating.Preferably, coatings are sufficiently durable to resist displacement bymechanical abrasion as well as weight loss. Preferred coatings have asubstantially uniform and smooth surface. Most preferably, coatingsmaintain a surface roughness (peak to valley) that is less than 50%,preferably 25%, of the total thickness of the coating. For instance, fora 10 micrometer thick coating, the surface is preferably not more thanabout 5 micrometers from its highest peak to its lowest valley. Alsopreferably, the coating roughness does not increase as a result ofmechanical abrasion of a type encountered in crimping and loading thecoated medical device into a delivery catheter.

FIGS. 10A-13B are optical micrographs of durable paclitaxel coatings onstents comprising various mixtures of dPTX and aPTX. The ratio ofamorphous to dihydrate paclitaxel in each coating was subsequentlydetermined by a monitoring a characteristic paclitaxel UV absorptionpeak (e.g., 227 nm) in an elution media in contact with the paclitaxelcoated stents. This determination was performed by dissolving thecoating in two different elution media separately contacted with thecoating. First, paclitaxel was eluted from the coated stents using afirst elution medium (the modified porcine serum) in which the dihydrateis substantially less soluble than the amorphous solid form ofpaclitaxel. Second, after elution of the dihydrate paclitaxel from thestents, the remaining paclitaxel was eluted from the coated stents usinga second elution medium (0.3% Sodium Dodecyl Sulfate) effective toreadily dissolve the remaining paclitaxel (presumed to be the moreslowly soluble dihydrate) in the coating (without the first elutionmedium). Based on the comparative solubility of the dPTX and aPTX solidforms in the first and second elution media (see, e.g., FIG. 6A andFIGS. 7A-7B), the concentration of paclitaxel in the elution media wasused to determine the ratio of solid forms present in the taxanecoatings on the stents.

A mixture of amorphous and dihydrate taxane therapeutic agent coatinghas a cloudy or spotted appearance (clear coating with white opaqueregions). FIG. 10A shows a 50× optical micrograph of a metal stentcoated with about 65% dihydrate paclitaxel (35% amorphous paclitaxel)coating prepared by untrasonic spray coating a 4.68 mM paclitaxelsolution in a 93% v methanol (7% water) solvent. FIG. 10B shows a 115×optical micrograph of the coating shown in FIG. 10A. The 65:35 w/wdPTX:aPTX coating has a largely cloudy and spotty appearance due to thepresence of the dihydrate solid form of paclitaxel. Opaque white regionsappear in the coating due to the mixture of the dihydrate (opaque,white) with lesser amounts of the amorphous (clear) solid form ofpaclitaxel.

FIG. 11A shows a 50× optical micrograph of an metal stent coated withabout 50% dihydrate paclitaxel (50% amorphous paclitaxel) coatingprepared by untrasonic spray coating a 4.68 mM paclitaxel solution in a94% v methanol (6% water) solvent. FIG. 11B shows a 115× opticalmicrograph of the coating shown in FIG. 11A. The 50:50 w/w dPTX:aPTXcoating has a clearer and less spotty appearance compared to the coatingin FIGS. 10A-10B due to the increased proportion of the amorphous solidform of paclitaxel. Regions of varying opacity in the coating resultfrom the mixture of the amorphous (clear) solid form of paclitaxel withthe dihydrate (opaque, white) solid form.

FIG. 12A shows a 50× optical micrograph of an metal stent coated withabout 40% dihydrate paclitaxel (60% amorphous paclitaxel) coatingprepared by untrasonic spray coating a 4.68 mM paclitaxel solution in a95% v methanol (5% water) solvent. FIG. 12B shows a 115× opticalmicrograph of the coating shown in FIG. 12A. The 40:60 w/w dPTX:aPTXcoating has a clearer and less spotty appearance than the coating inFIGS. 10A-10B due to the increased proportion of the amorphous solidform of paclitaxel. Regions of varying opacity in the coating resultfrom the mixture of the amorphous (clear) solid form of paclitaxel withthe dihydrate (opaque, white) solid form.

FIG. 13A shows a 50× optical micrograph of an metal stent coated withabout 100% amorphous paclitaxel coating prepared by untrasonic spraycoating a 4.68 mM paclitaxel solution in a 95% v methanol (5% water)solvent. FIG. 13B shows a 115× optical micrograph of the coating shownin FIG. 13A. The aPTX coating has a clearer appearance indicative of theamorphous (clear) solid form of paclitaxel.

Notably, as the dose of paclitaxel increases, more dihydrate solid formis typically needed to maintain a given level of durability. Forexample, a paclitaxel-only coating having a 50:50 ratio of thedihydrate:amorphous solid forms was durable at a dose of 3 μg/mm² butnot for a dose of 1 μg/mm². That is, paclitaxel coatings with greaterthan 50% dihydrate solid form were typically required to maintaindurability at the 1 μg/mm² coating that was comparable to the 3 μg/mm²coating.

Table 6 below provides examples of preferred abluminal paclitaxelcoatings on a 6×20 radially expandable vascular stent, showing therelationship between the composition of the spray solution and theresulting coating composition. Each coating is deposited usingultrasonic deposition according to Table 4 above at a temperature ofabout 87 F. The spray solution included the concentration of paclitaxelin Table 6 with methanol and water in a ratio that provides a desiredamount of the dihydrate solid form. As described by Table 3a and Table3b, increasing the amount of methanol relative to water resulted in lessdihydrate in the coating at any concentration of paclitaxel.

TABLE 6 Preferred Paclitaxel Coatings Preferred Concentration PaclitaxelDose Total Paclitaxel dPTX:aPTX for Paclitaxel in Spray (μg/mm²) (μg)durability (%:%) Solution (mM) 0.06 5 80:20 0.70 0.30 24 75:25 1.74 1.0074 70:30 2.34 3.00 219 50:50 4.68Medical Devices

The coatings may be applied to one or more surfaces of any implantablemedical device having any suitable shape or configuration.

The medical device may be adapted or selected for temporary or permanentplacement in the body for the prophylaxis or treatment of a medicalcondition. For example, such medical devices may include, but are notlimited to, stents, stent grafts, vascular grafts, balloon catheters,catheters, guide wires, balloons, filters (e.g. vena cava filters),cerebral aneurysm filler coils, intraluminal paving systems, sutures,staples, anastomosis devices, vertebral disks, bone pins, sutureanchors, hemostatic barriers, clamps, screws, plates, clips, slings,vascular implants, tissue adhesives and sealants, tissue scaffolds,myocardial plugs, pacemaker leads, valves (e.g. venous valves),abdominal aortic aneurysm (AAA) grafts, embolic coils, various types ofdressings, bone substitutes, intraluminal devices, vascular supports, orother known bio-compatible devices.

In general, intraluminal stents are preferred surfaces for use with thecoatings described herein. Stents may typically comprise a plurality ofapertures or open spaces between metallic filaments (including fibersand wires), segments or regions. Typical stent structures include: anopen-mesh network comprising one or more knitted, woven or braidedmetallic filaments; an interconnected network of articulable segments; acoiled or helical structure comprising one or more metallic filaments;and, a patterned tubular metallic sheet (e.g., a laser cut tube).Examples of suitable intraluminal stents include endovascular, biliary,tracheal, gastrointestinal, urethral, ureteral, esophageal and coronaryvascular stents. Although certain embodiments are described herein withreference to vascular stents, other embodiments relate to coatings onother types of stents.

The stent may be part of a stent graft, a bifurcated stent, a coronaryvascular stent, a urethral stent, a ureteral stent, a biliary stent, atracheal stent, a gastrointestinal stent, or an esophageal stent, forexample. More specifically, the stent may be, for example, a Wallstent,Palmaz-Shatz, Wiktor, Strecker, Cordis, AVE Micro Stent, Igaki-Tamai,Millenium Stent (Sahajanand Medical Technologies), Steeplechaser stent(Johnson & Johnson), Cypher (Johnson & Johnson), Sonic (Johnson &Johnson), BX Velocity (Johnson & Johnson), Flexmaster (JOMED) JoStent(JOMED), S7 Driver (Medtronic), R-Stent (Orbus), Tecnic stent (SorinBiomedica), BiodivYsio (Abbott), Trimaxx (Abbott), DuraFlex (AvantecVascular), NIR stent (Boston Scientific), Express 2 stent (BostonScientific), Liberte stent (Boston Scientific), Achieve (Cook/Guidant),S-Stent (Guidant), Vision (Guidant), Multi-Link Tetra (Guidant),Multi-Link Penta (Guidant), or Multi-Link Vision (Guidant). Someexemplary stents are also disclosed in U.S. Pat. No. 5,292,331 toBoneau, U.S. Pat. No. 6,090,127 to Globerman, U.S. Pat. No. 5,133,732 toWiktor, U.S. Pat. No. 4,739,762 to Palmaz, and U.S. Pat. No. 5,421,955to Lau. Desirably, the stent is a vascular stent such as thecommercially available Gianturco-Roubin FLEX-STENT®, GRII™, SUPRA-G,ZILVER or V FLEX coronary stents from Cook Incorporated (Bloomington,Ind.).

The stent or other medical device may be made of one or more suitablebiocompatible materials such as stainless steel, nitinol, MP35N, gold,tantalum, platinum or platinum irdium, niobium, tungsten, iconel,ceramic, nickel, titanium, stainless steel/titanium composite, cobalt,chromium, cobalt/chromium alloys, magnesium, aluminum, or otherbiocompatible metals and/or composites or alloys, or as carbon or carbonfiber. Other materials for medical devices, such as drainage stents orshunts, include cellulose acetate, cellulose nitrate, silicone,cross-linked polyvinyl alcohol (PVA) hydrogel, cross-linked PVA hydrogelfoam, polyurethane, polyamide, styrene isobutylene-styrene blockcopolymer (Kraton), polyethylene teraphthalate, polyurethane, polyamide,polyester, polyorthoester, polyanhydride, polyether sulfone,polycarbonate, polypropylene, high molecular weight polyethylene,polytetrafluoroethylene, or other biocompatible polymeric material, ormixture of copolymers thereof; polyesters such as, polylactic acid,polyglycolic acid or copolymers thereof, a polyanhydride,polycaprolactone, polyhydroxybutyrate valerate or other biodegradablepolymer, or mixtures or copolymers thereof; extracellular matrixcomponents, proteins, collagen, fibrin or other therapeutic agent, ormixtures thereof. Desirably, the device is made of stainless steel,cobalt-chromium or a nickel-titanium alloy (e.g., Nitinol).

The stent may be deployed according to conventional methodology, such asby an inflatable balloon catheter, by a self-deployment mechanism (afterrelease from a catheter), or by other appropriate means. The stent maybe formed through various methods, such as welding, laser cutting, ormolding, or it may consist of filaments or fibers that are wound orbraided together to form a continuous structure. The stent may also be agrafted stent in which the therapeutic agent is incorporated into thegraft material.

Methods of Treatment

Methods of treatment preferably include the step of inserting into apatient a coated medical device having any of the compositions and/orconfigurations described above. For example, when the medical device isa stent coated by the coating methods described above, the method oftreatment involves implanting the stent into the vascular system of apatient and allowing the therapeutic agent(s) to be released from thestent in a controlled manner, as shown by the drug elution profile ofthe coated stent.

In one preferred embodiment, the coated medical devices are implanted totreat peripheral vascular disease, for example by implanting the coatedmedical device in a peripheral artery. In one aspect, methods oftreating peripheral vascular disease (PVD) are provided. PVD is adisease of the lower extremities that may present various clinicalindications ranging from asymptomatic patients, to patients with chroniccritical limb ischemia (CLI) that might result in amputation and limbloss.

Methods of treating peripheral vascular disease, including critical limbischemia, preferably comprise the endovascular implantation of one ormore coated medical devices provided herein. Atherosclerosis underliesmany cases of peripheral vascular disease, as narrowed vessels thatcannot supply sufficient blood flow to exercising leg muscles may causeclaudication, which is brought on by exercise and relieved by rest. Asvessel narrowing increases, critical limb ischemia (CLI) can developwhen the blood flow does not meet the metabolic demands of tissue atrest. While critical limb ischemia may be due to an acute condition suchas an embolus or thrombosis, most cases are the progressive result of achronic condition, most commonly atherosclerosis. The development ofchronic critical limb ischemia usually requires multiple sites ofarterial obstruction that severely reduce blood flow to the tissues.Critical tissue ischemia can be manifested clinically as rest pain,nonhealing wounds (because of the increased metabolic requirements ofwound healing) or tissue necrosis (gangrene).

The coated medical device can be implanted in any suitable body vessel.Typical subjects (also referred to herein as “patients”) are vertebratesubjects (i.e., members of the subphylum cordata), including, mammalssuch as cattle, sheep, pigs, goats, horses, dogs, cats and humans. Sitesfor placement of the medical devices include sites where local deliveryof taxane therapeutic agents are desired. Common placement sites includethe coronary and peripheral vasculature (collectively referred to hereinas the vasculature). Other potential placement sites include the heart,esophagus, trachea, colon, gastrointestinal tract, biliary tract,urinary tract, bladder, prostate, brain and surgical sites, particularlyfor treatment proximate to tumors or cancer cells. Where the medicaldevice is inserted into the vasculature, for example, the therapeuticagent is may be released to a blood vessel wall adjacent the device, andmay also be released to downstream vascular tissue as well.

The configuration of the implantable frame can be selected based on thedesired site of implantation. For example, for implantation in thesuperficial artery, popliteal artery or tibial artery, frame designswith increased resistance to crush may be desired. For implantation inthe renal or iliac arteries, frame designs with suitable levels ofradial force and flexibility may be desired. Preferably, a coatedvascular stent is implanted in a non-coronary peripheral artery, such asthe iliac or renal arteries.

In one embodiment, a medical device comprising a balloon-expandableframe portion coated with a taxane therapeutic agent can beendoluminally delivered to a point of treatment within an infrapoplitealartery, such as the tibial or peroneal artery or in the iliac artery, totreat CLI. For treating focal disease conditions, coatedballoon-expandable medical devices can comprise an expandable frameattached to a coating. The frame can be also be formed from abioabsorbable material, or comprise a coating of the therapeutic agentmaterial over at least a portion of the frame. The frame can beconfigured to include a barb or other means of securing the medicaldevice to the wall of a body vessel upon implantation.

In another aspect, a coated medical device can be a self-expandingdevice such as a coated NITINOL stent coated with the taxane therapeuticagent, and configured to provide a desirable amount of outward radialforce to secure the medical device within the body vessel. The medicaldevice can be preferably implanted within the tibial arteries fortreatment of CLI. For instance, the coated medical device can beconfigured as a vascular stent having a self-expanding support frameformed from a superelastic self-expanding nickel-titanium alloy coatedwith a metallic bioabsorbable material and attached to a graft material.A self-expanding frame can be used when the body vessel to be stentedextends into the distal popliteal segment. The selection of the type ofimplantable frame can also be informed by the possibility of externalcompression of an implant site within a body vessel during flexion ofthe leg.

A consensus document has been assembled by clinical, academic, andindustrial investigators engaged in preclinical interventional deviceevaluation to set forth standards for evaluating drug-eluting stentssuch as those contemplated by the present invention. See “Drug-ElutingStents in Preclinical Studies—Recommended Evaluation From a ConsensusGroup” by Schwartz and Edelman (available at“http://www.circulationaha.org.”(incorporated herein by reference).

EXAMPLES

In the following examples, the equipment and reagents specified belowwere used:

TABLE 7 Manufacturer Equipment Name Manufacturer ID Vendor 1 μg BalanceMettler AX 26 VWR 10 μg Balance Mettler AX 105 DR VWR Top LoadingBalance Ohaus GT 4100 VWR (not avail.) Inline Spectrometer Agilent 8453Agilent Chemstation Agilent Version Agilent A.10.01 Coating SpectrometerPerkin Elmer Lambda 14 P Perkin Elmer 1 Coating Spectrometer PerkinElmer Lambda 45 Perkin Elmer 2 UV Winlab Perkin Elmer Version 5.1 PerkinElmer Cuvettes Perkin Elmer B0631077 VWR Electrostatic Coater TerronicsCustom Terronics MED Spray Badger Model 200 Ding-A-Ling Gun/Badger CookIncorporated EFD 780S-SS EFD Spray Gun Cook Incorporated EFD ValvemateEFD Spray Controller 7040 Microscope Leica MZ-16 Nuhsbaum Inc. Image ProPlus MediaCybernetics Version 5.1 Media Cybernetics Microsoft OfficeMicrosoft Version 2003 New Egg Stopwatch Private Label n/a VWR GlasswareKimball Various VWR Ethanol Aaper E 200 PP Aaper Methanol Sigma M 3641Sigma Dichloromethane Sigma 15,479-2 Sigma Water Ricca Chemical 9150-5VWR

Example 1 Preparation of Amorphous, Anhydrous and Dihydrate Paclitaxel

Bulk samples of amorphous, anhydrous and dihydrate paclitaxel solidforms were prepared by the methods described below.

Samples of bulk amorphous paclitaxel were prepared as follows: 1.01 g ofpaclitaxel (Phytogen Life Sciences) was dissolved in 5 mLdichloromethane (Mallinckrodt) while agitating to form a paclitaxelsolution; the paclitaxel solution was left open to air at about 23° C.for about 10 hours to permit evaporation of the dichloromethane andformation of amorphous paclitaxel. The melting temperature of theamorphous paclitaxel was 209-215° C.

Samples of bulk anhydrous paclitaxel were prepared as follows: 1.06 g ofpaclitaxel (Phytogen Life Sciences) were dissolved in 40 mL methanol(Sigma Aldrich, 99.93% HPLC Grade) while sonnicating the container andinversion of the container to form a pacliatxel solution; about 2 mL ofhexane (Sigma Aldrich) was added to the paclitaxel solution, and thesolution was placed in a freezer at about −20° C. overnight(approximately 10 hours) to form anhydrous crystalline paclitaxel. Themelting temperature of the anhydrous paclitaxel was 190-210° C.

Samples of dihydrate paclitaxel were prepared as follows: 1.09 gpaclitaxel (Phytogen Life Sciences) were dissolved in 25 mL methanolwhile sonnicating the container to form a paclitaxel solution; about 5mL of water was added to the paclitaxel solution; and the sample wasplaced in a freezer at about −20° C. overnight to form dihydratecrystals. The melting temperature of the dihydrate crystal was 209-215°C. Subsequently, the sample was sealed under vacuum to 0.025 torr for2.5 hours to remove residual solvent. Dihydrate paclitaxel samples werealso prepared as follows: 50.08 g paclitaxel (Phytogen Life Sciences)was dissolved in 1.1 L methanol to form a solution; 275 mL water wassubsequently added to the methanol solution in a drop-wise fashion toform a precipitate that was refrigerated at about −20° C. overnight(about 10 hours); the resulting solid precipitate was filtered,dissolved in 1500 mL methanol and 375 mL water, and was subsequentlyadded in a drop-wise fashion; the resulting crystals were recrystallizeda third time using 1200 mL methanol with 300 mL water; and the resultingdihydrate crystals were collected.

Example 2 Ultraviolet (UV) Spectra of Bulk Paclitaxel Samples

The three solid samples prepared in Example 1 (amorphous, dihydrate andanhydrous paclitaxel) were dissolved in ethanol to form spray solutions.The ultraviolet spectra of each of the three samples were taken (AgilentIn-Line UV Spectrophotometer), to obtain three spectra that wereindistinguishable from the spectrum 100 shown in FIG. 2. The spectra allincluded a peak at 227 nm indicative of the taxane core structure in thepaclitaxel, indicating that the paclitaxel solid forms of Example 1 werenot distinguishable from each other based on UV spectra of thepaclitaxel in solution.

Example 3 Infrared Spectra of Bulk Paclitaxel Samples

FTIR Infrared spectra each of the samples prepared in Example 1 wereobtained following procedure: a pellet of KBr was made by grinding thepaclitaxel crystal with KBr using a mortar and pestel at roomtemperature (about 23° C.); the resulting solid was placed under vacuumto remove residual methanol solvent (0.025 mmHg); and a spectra wasrecorded of the paclitaxel analyte. Representative spectra of each solidform of paclitaxel are provided in FIGS. 3A-3C, as discussed above.Infrared spectra may also be obtained using Attenuated Total ReflectionInfrared (ATR-IR) from a coating or a small sample of a solid taxanesample from a coating. One suitable ATR-IR apparatus is the PerkinElmerHorizontal ATR model L1200361.

Example 4 Spray Gun Coating of Stents with Paclitaxel

Paclitaxel coatings comprising amorphous paclitaxel, dihydratepaclitaxel and mixtures thereof were deposited by spraying a solution ofpaclitaxel in ethanol from an EFD 780S-SS spray valve system (EFD, Inc.,East Providence, R.I.) (hereinafter, “spray gun”). In spray coating withthe EFD 780S-SS spray valve system, decreasing the atomization pressure(larger spray particle size), increasing the fluid pressure (increasingthe flow rate) and/or humidity during the spraying process favor theincreased formation of water solvated dihydrate solid forms overamorphous or anhydrous forms. Increased temperature is also believed tofavor formation of the solvated dihydrate solid forms. Increasing thetank pressure can result in a higher flowrate from the spray gun nozzle,and favor the deposition of more of the dihydrate solid form. Increasingthe atomization pressure can result in a finer mist being sprayed fromthe spray gun, favoring the deposition of more amorphous taxanetherapeutic coatings, with less dihydrate solid form.

Overall, typical spray parameters for deposition of a taxane therapeuticagent with the EFD 780S-SS spray valve system include: (1) a relativehumidity of between about 5% and about 80% (depending on the solid formof the coating desired) (2) an atomization pressure of between about2.00 psi and 25.00 psi (depending on the type of solid form of coatingdesired); (3) an ambient temperature of about 65° F. to about 85° F.;and (4) a fluid pressure of between about 1.00 psi and 10.00 psi.

Spray coating process conducted under one or preferably more of thefollowing conditions with the EFD 780S-SS spray valve system resulted inincreased formation of a dihydrate taxane therapeutic agent solid formin a coating: (1) a relative humidity of greater than 40% and (2) anatomization pressure of less than 10 psi. A dihydrate taxane therapeuticagent coating has a white, cloudy or opaque appearance. The dihydratetaxane therapeutic agent coatings were made by: dissolving solid 4 gpaclitaxel in 1 L ethanol to form a solution, and spraying the solutiononto a medical device with an atomization pressure of 10 psi or less inan environment having a relative humidity of 40% or greater. Thespraying step was performed at a temperature of about 75° F. or greater,and with a fluid pressure of between about 1.00 and 5.00 psi. Dihydratepaclitaxel (dPTX) coatings were deposited under the followingconditions: (1) 4.0 g/L PTX (4.68 mM) in ethanol spray solution, 44%relative humidity, 12.00 psi atomization pressure, 2.50 psi fluid (tank)pressure and 80° F. ambient temperature; or (2) 4.0 g/L PTX in ethanolspray solution, 55% relative humidity, 5.00 psi atomization pressure,1.00 psi fluid (tank) pressure and 70° F. ambient temperature.

Coatings comprising mixtures of amorphous paclitaxel (aPTX) anddihydrate paclitaxel (dPTX) were deposited under the followingconditions: (1) 4.0 g/L PTX in ethanol spray solution, 30% relativehumidity, 13 psi atomization pressure, 1.5 psi fluid (tank) pressure and70° F. ambient temperature. The flow rate of the solution through thespray gun was about 8 mL/min. The spray gun was passed over the stentsfor multiple passes until a desired dose of paclitaxel was coated on theabluminal surface of the stents. The paclitaxel coatings containedbetween 0.2 and 4 μg of the taxane therapeutic agent per mm² of theabluminal surface area of the stent, depending on the number of passesof the spray gun. For example, a 6×20 mm stent may be coated was coatedwith a total of 219 μg of paclitaxel at an abluminal surfaceconcentration of about 3 μg/mm² of paclitaxel. A 3×20 mm stent wascoated with a total of about 120 μg of paclitaxel at the same abluminalsurface concentration of about 3 μg/mm² of paclitaxel.

Example 5 Ultrasonic Spray Coating of Stents with Paclitaxel

Stents with coatings consisting of paclitaxel taxane therapeutic agentcoatings including both the dihydrate solid form and in the amorphoussolid forms of paclitaxel were prepared by spray coating a solutioncomprising paclitaxel, methanol and water. A paclitaxel solution inmethanol and water was prepared. Specifically, a 1.74 mM paclitaxelsolution was prepared in 68% methanol by dissolving 7.43 mg ofpaclitaxel in 5 mL of previously made solution of 68% methanol 32%water. The solution was sprayed from an ultrasonic spray gun (Sono-tekModel 06-04372) in a glove box. Before spraying, the glove box waspurged with nitrogen at 20 psi for 15 minutes. The atmosphere in theglove box was adjusted until the oxygen meter reads a constant 200 ppmwithin the glove box. The heat in the glovebox was set to 31° C. (88°F.), the air shroud to 2.0 psi and the ultrasonic power to 1.0 W. Thepaclitaxel solution was loaded into a syringe and place on the syringepump in the ultrasonic coating apparatus and a bare metal stent (6×20ZILVER, Cook Inc., Bloomington, Ind.) was mounted on a mandrel alignedwith the spray nozzle. The solution was sprayed onto a stent using a 60kHz nozzle at a flow rate of 0.03 mL/min, a coating velocity of 0.025in/sec, a nozzle power of 1.0 W, a process gas pressure of 2.0 psi, anda distance from the nozzle to the stent of about 12 mm, while rotatingthe stent with an axial rotation rate of 60 rpm. Only the abluminalsurface of the stent was coated.

Example 6 Elution of Paclitaxel-Coated Stents in Porcine Serum

Stents with coatings consisting of paclitaxel taxane therapeutic agentsin both the dihydrate solid form and in the amorphous form were preparedby spray coating a solution comprising various amounts of paclitaxel,methanol and water. A 2.34 mM paclitaxel solution in 88% methanol and12% water (v) was made with a total volume of about 10 mL (20.04 mgpaclitaxel). Twelve (12) 6×20 ZILVER (Cook Inc., Bloomington, Ind.)stents were spray coated using the ultrasonic coating procedure ofExample 5 and the parameters in Table 8 below. Table 8 also shows theamount of paclitaxel coated on each stent.

TABLE 8 Coating Parameters for Stents Coated with 2.34 mM PaclitaxelCoating Solution 2.34 mM PTX in 88% MeOH/H₂O Stents 1-3 4-6 7-9 10-12Relative Humidity (%)  8.7-13.3 7.3-8.5 7.1-8.3 7.4-8.2 Temperature(degrees F.) 82.4-83.1 83.1 83.3-83.4 83.7-84.0 Target Dose (μg) 74Actual Dose (μg) 84 ± 5.89 Flow Rate (mL/min) 0.03 Loops 5 Air Shroud(psi) 1.0 Linear Velocity (in/sec) 0.025 Rotational Velocity (rpm) 60Oxygen Content (ppm) 145-155 Power (Watts) 0.8 Nozzle Distance from 8Stent (mm)

FIG. 14 shows an elution graph 1000 comparing a first elution profile1002 for a 100% amorphous paclitaxel coating (formed by spray coating anethanol-paclitaxel according to Example 4) compared to a second elutionprofile 1004 obtained as the average of the 12 stent coatings accordingto Table 8 (containing about 50% dihydrate paclitaxel) (both in porcineserum). Increasing the amount of dihydrate resulted in sustained releaseof the paclitaxel in the second elution profile 1004 compared to thefirst elution profile 1002. FIG. 14 was obtained from a coated vascularstent having an amorphous paclitaxel (1002) or a 50% dihydrate: 50%amorphous paclitaxel coating (1004) obtained in separate experimentsduring the continuous flow of a porcine serum elution medium. Thecoatings did not comprise a polymer. The amount of paclitaxel in theelution medium was measured by UV absorption at 227 nm. The firstelution profile 1002 shows substantially all of the amorphous paclitaxeleluting within less than about 5 hours. The second elution profile 1004in porcine serum elution medium showed about 60% of the paclitaxelcoating eluted after about 25 hours and about 80% of the paclitaxelcoating eluted from the coating after 75 hours.

Example 7 Elution of Paclitaxel-Coated Stents in HCD

Stents with coatings consisting of paclitaxel taxane therapeutic agentsin both the dihydrate solid form and in the amorphous form were preparedby spray coating a solution comprising various amounts of paclitaxel,methanol and water. First, a first coating solution of 4.68 mMpaclitaxel solution in 100% ethanol was prepared with 19.96 mgpaclitaxel in 5 mL ethanol. Second, a second solution of 4.68 mMpaclitaxel in 93% methanol and 7% water (v) was made with a total volumeof about 5 mL (19.99 mg paclitaxel). Five (5) 6×20 ZILVER (Cook Inc.,Bloomington, Ind.) stents were spray coated with the first spraysolution and five (5) more 6×20 ZILVER (Cook Inc., Bloomington, Ind.)stents were spray coated with the second spray solution. All coating wasperformed on the abluminal surface only using the ultrasonic coatingprocedure of Example 5 and the parameters in Table 9 below. Table 9 alsoshows the amount of paclitaxel coated on each stent. Coatings formedfrom the first solution (ethanol) contained 93% amorphous paclitaxel, 7%dihydrate paclitaxel; coatings formed from the second solution(methanol/water) contained about 82% dihydrate and 18% amorphouspaclitaxel.

TABLE 9 Coating Parameters for Stents Coated with 4.68 mM PaclitaxelCoating Solvent EtOH 93% MeOH/H₂O Stent #s 100-102 103-105 200-202203-205 Temperature (degrees F.) 79.2 79.4-79.5 78.3-79.0 77.2-78.1Oxygen Content (ppm) 135-165 125-145 135-145 135-180 Relative Humidity(%) 0.0 0.0-0.8 0.0 Power (Watts) 1.1 0.8 Actual Dose (μg) 195 ± 17 301± 10 Flow Rate (mL/min) 0.03 Loops 7 Air Shroud (psi) 1.0 LinearVelocity (in/sec) 0.025 Rotational Velocity (rpm) 60 Nozzle Distancefrom 8 Stent (mm) Target Dose (μg) 219

FIG. 15 shows an elution graph 1100 obtained in a 0.5% aqueous HCDsolution, comparing a first elution profile 1102 from the coatingsformed from the 93% amorphous paclitaxel coating deposited from thefirst solution (formed by ultrasonic spray coating an according toExample 5, except as indicated in Example 7) compared to a secondelution profile 1104 obtained from the stent coatings from the 82%dihydrate coating deposited from the second solution (formed byultrasonic spray coating an according to Example 5, except as indicatedin Example 7). The coatings did not comprise a polymer. The amount ofpaclitaxel in the elution medium was measured by UV absorption at 227nm. The first elution profile 1102 shows a more rapid elution rate thanthe second elution profile 1104. Data points 1105 were obtained bycontacting the coated stent formed from the second solution with 100%ethanol after obtaining the second elution profile 1104, resulting inrapid release of all remaining paclitaxel from the coating.

We claim:
 1. A method of delivering a taxane therapeutic agent to a body vessel of a patient comprising: inserting a coated implantable device into the body vessel, wherein the coated implantable device comprises at least one surface having a coating comprising the taxane therapeutic agent in a first taxane solid form characterized by a vibrational spectrum comprising at least two peaks between 1735 and 1705 cm⁻¹ and a solubility of less than 20% wt. after 24 hours in porcine serum at 37° C., and in a second taxane solid form characterized by a vibrational spectrum comprising one peak between 1735 and 1705 cm⁻¹ and a solubility of greater than 50% wt. after 24 hours in porcine serum at 37° C., wherein at least 10% of the taxane therapeutic agent is present in the first taxane solid form positioning the coated implantable device within the body vessel; and radially expanding the coated implantable device within the body vessel so as to place the coated implantable device in contact with a portion of a wall of the body vessel in a manner effective to deliver at least a portion of the taxane therapeutic agent to the wall of the body vessel.
 2. The method of claim 1, wherein the taxane therapeutic agent is paclitaxel.
 3. The method of claim 2, wherein the second taxane solid form is amorphous paclitaxel.
 4. The method of claim 2, wherein the first taxane solid form is dihydrate paclitaxel.
 5. The method of claim 1, wherein the coated implantable device is a radially expandable vascular stent.
 6. The method of claim 1, wherein the coated implantable device is a balloon catheter.
 7. The method of claim 1, wherein the coating comprises at least two layers, wherein each layer comprises at least one of the first taxane solid form and the second taxane solid form.
 8. The method of claim 1, wherein the coating is free of a polymer.
 9. The method of claim 1, wherein the body vessel is a vascular vessel.
 10. The method of claim 9, wherein the vascular vessel is a peripheral vessel.
 11. The method of claim 9, wherein the vascular vessel is a coronary vessel.
 12. A method of delivering a taxane therapeutic agent to a vascular vessel of a patient comprising: inserting a coated implantable device into the vascular vessel using a means for intralumenal delivery, wherein the coated implantable device comprises at least one surface having a coating comprising the taxane therapeutic agent in a first taxane solid form, wherein the first taxane solid form is dihydrate paclitaxel, and in a second taxane solid form, wherein the second taxane solid form is amorphous paclitaxel, wherein at least 10% of the taxane therapeutic agent is present in the first taxane solid form, positioning the coated implantable device within the vascular vessel; and radially expanding the coated implantable device within the vascular vessel so as to place the coated implantable device in contact with a portion of a wall of the vascular vessel in a manner effective to deliver at least a portion of the taxane therapeutic agent to the wall of the vascular vessel wherein the coated implantable device is a radially expandable vascular stent or a balloon catheter.
 13. The method of claim 12, wherein the vascular vessel is a peripheral vessel.
 14. The method of claim 12, wherein the vascular vessel is a coronary vessel.
 15. A coated implantable medical device having at least one surface and comprising a coating on the at least one surface, the coating comprising: the taxane therapeutic agent in a first taxane solid form, wherein the first taxane solid form is dihydrate paclitaxel, and in a second taxane solid form, wherein the second taxane solid form is amorphous paclitaxel, wherein at least 10% of the taxane therapeutic agent is present in the first taxane solid form, wherein the coated implantable medical device is a radially expandable vascular stent or a balloon catheter.
 16. The coated implantable medical device of claim 15, wherein the coating is free of a polymer.
 17. The coated implantable medical device of claim 15, wherein the coating comprises at least two layers, wherein each layer comprises at least one of the first taxane solid form and the second taxane solid form. 